Alpha ketoamide compounds as cysteine protease inhibitors

ABSTRACT

The present invention is directed to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a CON of 12/337,596 Dec. 17, 2008, now Pat. No.7,696,250, which is a CON of 11/384,023 Mar. 17, 2006, now Pat. No.7,488,848, which claims benefit of 60/663,970 Mar. 21, 2005, and claimsbenefit of 60/684,623 May. 24, 2005.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH OR DEVELOPMENT

NOT APPLICABLE

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

NOT APPLICABLE

FIELD OF THE INVENTION

The present invention is directed to compounds that are inhibitors ofcysteine proteases, in particular, cathepsins B, K, L, F, and S and aretherefore useful in treating diseases mediated by these proteases. Thepresent invention is also directed to pharmaceutical compositionscomprising these compounds and processes for preparing them.

STATE OF THE ART

Cysteine proteases represent a class of peptidases characterized by thepresence of a cysteine residue in the catalytic site of the enzyme.Cysteine proteases are associated with the normal degradation andprocessing of proteins. The aberrant activity of cysteine proteases,e.g., as a result of increased expression or enhanced activation,however, may have pathological consequences. In this regard, certaincysteine proteases are associated with a number of disease states,including arthritis, muscular dystrophy, inflammation, tumor invasion,glomerulonephritis, malaria, periodontal disease, metachromaticleukodystrophy and others. For example, increased cathepsin B levels andredistribution of the enzyme are found in tumors; thus, suggesting arole for the enzyme in tumor invasion and metastasis. In found intumors; thus, suggesting a role for the enzyme in tumor invasion andmetastasis. In addition, aberrant cathepsin B activity is implicated insuch disease states as rheumatoid arthritis, osteoarthritis,pneumocystis carinii, acute pancreatitis, inflammatory airway diseaseand bone and joint disorders.

The prominent expression of cathepsin K in osteoclasts andosteoclast-related multinucleated cells and its high collagenolyticactivity suggest that the enzyme is involved in osteoclast-mediated boneresorption and, hence, in bone abnormalities such as occurs inosteoporosis. In addition, cathepsin K expression in the lung and itselastinolytic activity suggest that the enzyme plays a role in pulmonarydisorders as well.

Cathepsin L is implicated in normal lysosomal proteolysis as well as inseveral disease states, including, but not limited to, metastasis ofmelanomas. Cathepsin S is implicated in Alzheimer's disease and certainautoimmune disorders, including, but not limited to juvenile onsetdiabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease,myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis,neuropathic pain, and Hashimoto's thyroiditis. In addition, cathepsin Sis implicated in: allergic disorders, including, but not limited toasthma; and allogeneic immune reponses, including, but not limited to,rejection of organ transplants or tissue grafts.

In view of the number of diseases wherein it is recognized that anincrease in cysteine protease activity contributes to the pathologyand/or symptomatology of the disease, molecules which inhibit theactivity of this class of enzymes, in particular molecules which inhibitcathepsins B, K, L, F, and/or S, will therefore be useful as therapeuticagents.

SUMMARY OF THE INVENTION

In one aspect, this invention is directed to a compound of Formula (I):

where:

R¹ is hydrogen or alkyl;

R² is cycloalkyl, cycloalkylalkyl, aralkyl, heteroaryl, or heteroaralkyloptionally substituted with one or two substitutents independentlyselected from alkyl, alkoxy, or halo;

R³ is hydrogen, alkyl or alkoxyalkyl;

R⁴ is alkyl; or

R³ and R⁴ together with the carbon atom to which they are attached formcycloalkylene optionally substituted with one to four fluoro orheterocycloalkylene optionally substituted with alkyl, alkoxyalkyl,hydroxyalkyl, acyl, cycloalkyl, cycloalkylalkyl, or haloalkyl;

R⁵ is alkyl, haloalkyl optionally substituted with cycloalkyl, aryl,heteroaryl, or heterocycloalkyl, cycloalkylalkyl, aralkyl,heteroaralkyl, heterocycloalkylalkyl, -(alkylene)-X—R⁹ (where X is —O—,—S—, —SO—, —SO₂—, —CONH—, —NHCO—, or —NHSO₂— and R⁹ is alkyl, haloalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocycloalkyl, or heterocycloalkylalkyl), or-(alkylene)-X¹-(haloalkylene)-R¹⁰ (where X¹ is —O—, —S—, —SO—, —SO₂—,—CONH—, —NHCO—, or —NHSO₂— and R¹⁰ is cycloalkyl, aryl, heteroaryl, orheterocycloalkyl), wherein the aromatic or alicyclic ring in R⁵ isoptionally substituted with one, two, or three R^(a) independentlyselected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano,halo, carboxy, or alkoxycarbonyl; or optionally substituted with one ortwo R^(b) independently selected from hydrogen, alkyl, haloalkyl,alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and oneR^(c) selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, acyl, acylalkyl,aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl,heteroaralkyloxycarbonyl, heterocycloalkyloxycarbonyl,cycloalkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aminocarbonyl, aminosulfonyl, or —SO₂R¹¹ (where R¹¹ isalkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl); and furtherwherein the aromatic or alicyclic ring in R^(c) is optionallysubstituted with one, two, or three R^(d) independently selected fromalkyl, alkylsulfonyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo;

R⁶ is haloalkyl;

R⁷ is hydrogen, alkyl, or haloalkyl; and

R⁸ is hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryl,heterocycloalkyl attached via a carbon atom wherein the aromatic oralicyclic ring in R⁸ is optionally substituted with one, two, or threeR^(e) independently selected from alkyl, halo, haloalkyl, hydroxy,alkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, carboxy, cyano,alkylsulfonyl, alkylsulfonylamino, aminocarbonyl, or aminosulfonyl; or

a pharmaceutically acceptable salts thereof.

In a second aspect, this invention is directed to a pharmaceuticalcomposition comprising a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in admixture with one or more suitableexcipients.

In a third aspect, this invention is directed to a method for treating adisease in an animal mediated by cysteine proteases, in particularcathepsin S, which method comprises administering to the animal apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula (I) or a pharmaceutically acceptable saltthereof in admixture with one or more suitable excipients.

In a fourth aspect, this invention is directed to processes forpreparing compounds of Formula (I).

In a fifth aspect, this invention is directed to a method of treating apatient undergoing a therapy wherein the therapy causes an immuneresponse, preferably a deleterious immune response, in the patientcomprising administering to the patient a compound of Formula (I) or apharmaceutically acceptable salt thereof. Preferably, the immuneresponse is mediated by MHC class II molecules. The compound of thisinvention can be administered prior to, simultaneously, or after thetherapy. Preferably, the therapy involves treatment with a biologic.Preferably, the therapy involves treatment with a small molecule.

Preferably, the biologic is a protein, preferably an antibody, morepreferably a monoclonal antibody. More preferably, the biologic isRemicade®, Refacto®, Referon-A®, Factor VIII, Factor VII, Betaseron®,Epogen®, Enbrel®, Interferon beta, Botox®, Fabrazyme®, Elspar®,Cerezyme®, Myobloc®, Aldurazyme®, Verluma®, Interferon alpha, Humira®,Aranesp®, Zevalin® or OKT3.

Preferably, the treatment involves use of heparin, low molecular weightheparin, procainamide or hydralazine.

In a sixth aspect, this invention is directed to a method of treatingimmune response in an animal that is caused by administration of abiologic to the animal which method comprises administering to theanimal in need of such treatment a therapeutically effective amount of acompound of Formula (I) or a pharmaceutically acceptable salt thereof.

In a seventh aspect, this invention is directed to a method ofconducting a clinical trial for a biologic comprising administering toan individual participating in the clinical trial a compound of Formula(I) or a pharmaceutically acceptable salt thereof with the biologic.

In an eighth aspect, this invention is directed to a method ofprophylactically treating a patient undergoing treatment with a biologicwith a compound of Formula (I) or a pharmaceutically acceptable saltthereof to treat the immune response caused by the biologic in thepatient.

In a ninth aspect, this invention is directed to a method of determiningthe loss in the efficacy of a biologic in an animal due to the immuneresponse caused by the biologic comprising administering the biologic tothe animal in the presence and absence of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In a tenth aspect, this invention is directed to a method of improvingefficacy of a biologic in an animal comprising administering thebiologic to the animal with a compound of Formula (I) or apharmaceutically acceptable salt thereof.

In an eleventh aspect, this invention is directed to the use of acompound of Formula (I) or a pharmaceutically acceptable salt thereoffor the manufacture of a medicament. Preferably, the medicament is foruse in the treatment of a disease mediated by Cathepsin S.

In a twelfth aspect, this invention is directed to the use of a compoundof Formula (I) or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for combination therapy with a biologic,wherein the compound of this invention treats the immune response causedby the biologic. Preferably, the compound(s) of the invention isadministered prior to the administration of the biological agent.Preferably, the compound(s) of the invention is administeredconcomitantly with the biological agent. Preferably, the compound(s) ofthe invention is administered after the administration of the biologicalagent.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this Application and have thefollowing meanings.

“Alicyclic” means a moiety characterized by arrangement of the carbonatoms in closed non-aromatic ring structures e.g., cycloalkyl andheterocycloalkyl rings as defined herein.

“Alkyl” represented by itself means a straight or branched, saturatedaliphatic radical containing one to eight carbon atoms, unless otherwiseindicated e.g., alkyl includes methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, isobutyl, tert-butyl, and the like.

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated aliphatic, divalent radical having the number of one to sixcarbon atoms, e.g., methylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene(—CH₂CH₂CH₂—), tetramethylene (—CH₂CH₂CH₂CH₂—) 2-methyltetramethylene(—CH₂CH(CH₃)CH₂CH₂—), pentamethylene (—CH₂CH₂CH₂CH₂CH₂—), and the like.

“Alkylsulfonyl” means —SO₂R radical where R is alkyl as defined hereine.g., methylsulfonyl, ethylsulfonyl, and the like.

“Alkylsulfonylamino” means —NHSO₂R radical where R is alkyl as definedherein e.g., methylsulfonylamino, ethylsulfonylamino, and the like.

“Alkoxy” refers to a —OR radical where R is an alkyl group as definedabove e.g., methoxy, ethoxy, and the like.

“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with at least one alkoxy group, preferablyone or two alkoxy groups, as defined above, e.g., 2-methoxy-ethyl, 1-,2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

“Alkoxycarbonyl” refers to a —C(O)OR radical where R is an alkyl groupas defined above e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

“Aminoalkyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbons substituted with at least one, preferably one or two, —NRR′where R is hydrogen, alkyl, acyl, hydroxyalkyl, alkoxyalkyl, aryl,aralkyl, heteroaryl, heteroaralkyl or heterocycloalkylalkyl and R′ ishydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heterocycloalkylalkyl, cycloalkyl, cycloalkylalkyl,aminocarbonyl, or aminosulfonyl as defined herein e.g., aminomethyl,methylaminoethyl, dimethylaminoethyl, 1,3-diaminopropyl,acetylaminopropyl, and the like.

“Acyl” refers to a —COR radical where R is hydrogen, alkyl, haloalkyl,cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, orheterocycloalkyl as defined herein, e.g., formyl, acetyl,trifluoroacetyl, benzoyl, piperazin-1-ylcarbonyl, and the like. When Ris alkyl it is referred to in this application as alkylcarbonyl.

“Acylalkyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbons substituted with at least one, preferably one or two, acylgroup(s) as defined herein e.g., methylcarbonylmethyl, benzoylethyl,piperidin-1-ylcarbonylmethyl or ethyl, and the like.

“Aminocarbonyl” means —CONRR′ radical where R and R′ are independentlyselected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,or heterocycloalkylalkyl or R and R′ together with the nitrogen atom towhich they are attached form heterocycloamino as defined herein.

“Aminosulfonyl” means —SO₂NRR′ radical where R and R′ are independentlyselected from hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,or heterocycloalkylalkyl or R and R′ together with the nitrogen atom towhich they are attached form heterocycloamino as defined herein.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” refers to a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp² hybridizedand the total number of pi electrons is equal to 4n+2.

“Aryl” refers to a monocyclic or fused bicyclic ring assembly containing6 to 10 ring carbon atoms wherein each ring is aromatic e.g., phenyl ornaphthyl.

“Aryloxy” refers to a —O—R radical where R is aryl as defined abovee.g., phenoxy, napthyloxy, and the like.

“Aryloxycarbonyl” refers to a —C(O)OR radical where R is aryl as definedabove e.g., phenyloxycarbonyl, naphthyloxycarbonyl, and the like.

“Aralkyl” refers to a -(alkylene)-R radical where R is aryl as definedabove e.g., benzyl, phenethyl, and the like.

“Aralkyloxy” refers to a —O—R radical where R is aralkyl as definedabove e.g., benzyloxy, phenethyloxy, and the like.

“Aralkyloxycarbonyl” refers to a —C(O)OR radical where R is aralkyl asdefined above e.g., benzyloxycarbonyl, phenethyloxycarbonyl, and thelike.

“Biologic” means a therapeutic agent originally derived from livingorganisms for the treatment or management of a disease. Examplesinclude, but are not limited to, proteins (recombinant and plasmaderived), monoclonal or polyclonal, humanized or murine antibodies,toxins, hormones, and the like. Biologics are currently available forthe treatment of a variety of diseases such as cancer, rheumatoidarthritis, and hemophilia.

“Carboxy” refers to —C(O)OH radical.

“Cycloalkyl” refers to a monovalent saturated monocyclic ring containingthree to eight ring carbon atoms e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and the like.

“Cycloalkylalkyl” refers to a -(alkylene)-R radical where R iscycloalkyl as defined above e.g., cyclopropylmethyl, cyclobutylethyl,cyclobutylmethyl, and the like.

“Cycloalkyloxycarbonyl” refers to a —C(O)OR radical where R iscyccloalkyl as defined above e.g., cyclopropyloxycarbonyl,cyclopentyloxycarbonyl, and the like.

“Cycloalkylene” refers to a divalent saturated monocyclic ringcontaining three to eight ring carbon atoms. For example, the instancewherein “R³ and R⁴ together with the carbon atom to which both R¹ and R²are attached form cycloalkylene” includes, but is not limited to, thefollowing:

and the like.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Derived” means a similar agent can be traced to.

“Deleterious immune response” means an immune response that preventseffective treatment of a patient or causes disease in a patient. As anexample, dosing a patient with a murine antibody either as a therapy ora diagnostic agent causes the production of human antimouse antibodiesthat prevent or interfere with subsequent treatments. The incidence ofantibody formation versus pure murine monoclonals can exceed 70%. (seeKhazaeli, M. B. et al. J. Immunother. 1994, 15, pp 42-52; Dillman R. O.et al. Cancer Biother. 1994, 9, pp 17-28; and Reinsberg, J. Hybridoma.1995, 14, pp 205-208). Additional examples of known agents that sufferfrom deleterious immune responses are blood-clotting factors such asfactor VIII. When administered to hemophilia A patients, factor VIIIrestores the ability of the blood to clot. Although factor VIII is ahuman protein, it still elicits an immune response in hemophiliacs asendogenous factor VIII is not present in their blood and thus it appearsas a foreign antigen to the immune system. Approximately 29-33% of newpatients will produce antibodies that bind and neutralize thetherapeutically administered factor VIII (see Lusher J. M. Semin ThrombHemost. 2002, 28(3), pp 273-276). These neutralizing antibodies requirethe administration of larger amounts of factor VIII in order to maintainnormal blood clotting parameters; an expensive regimen of treatment inorder to induce immune tolerance (see Briet E et al. Adv. Exp. Med. Bio.2001, 489, pp 89-97). Another immunogenic example is adenoviral vectors.Retroviral therapy remains experimental and is of limited utility. Onereason is that the application of a therapeutic virus generates animmune response capable of blocking any subsequent administration of thesame or similar virus (see Yiping Yang et al. J. of Virology. 1995, 69,pp 2004-2015). This ensures that retroviral therapies must be based onthe transient expression of a protein or the direct incorporation ofviral sequence into the host genome. Directed research has identifiedmultiple viral neutralizing epitopes recognized by host antibodies (seeHanne, Gahery-Segard et al. J. of Virology 1998. 72, pp 2388-2397)suggesting that viral modifications will not be sufficient to overcomethis obstacle. This invention will enable a process whereby anadenoviral therapy will have utility for repeated application. Anotherexample of an immunogenic agent that elicits neutralizing antibodies isthe well-known cosmetic agent Botox. Botulin toxin protein, is purifiedfrom the fermentation of Clostridium botulinum. As a therapeutic agent,it is used for muscle disorders such as cervical dystonia in addition tocosmetic application. After repeated exposure patients generateneutralizing antibodies to the toxin that results in reduced efficacy(see Birklein F. et al. Ann Neurol. 2002, 52, pp 68-73 and Rollnik, J.D. et al. Neurol. Clin. Neurophysiol. 2001, 2001(3), pp 2-4). A“deleterious immune response” also encompasses diseases caused bytherapeutic agents. A specific example of this is the immune response totherapy with recombinant human erythropoietin (EPO). Erythropoietin isused to stimulate the growth or of red cells and restore red blood cellcounts in patients who have undergone chemotherapy or dialysis. A smallpercentage of patients develop antibodies to EPO and subsequently areunresponsive to both therapeutically administered EPO and their ownendogenous EPO (see Casadevall, N. et al., NEJM. 2002, 346, pp 469-475).They contract a disorder, pure red cell aplasia, in which red blood cellproduction is severely diminished (see Gershon S. K. et. al. NEJM. 2002,346, pp 1584-1586). This complication of EPO therapy is lethal ifuntreated. Another specific example is the murine antibody, OKT3(a.k.a., Orthoclone) a monoclonal antibody directed towards CD-3 domainof activated T-cells. In clinical trials 20-40% of patients administeredOKT3 produce antibodies versus the therapy. These antibodies, besidesneutralizing the therapy, also stimulate a strong host immune reaction.The immune reaction is severe enough that patients with high titers ofhuman anti-mouse antibodies are specifically restricted from taking thedrug (see Orthoclone package label). A final example is a human antibodytherapeutic. Humira® is a monoclonal antibody directed against TNF andis used to treat rheumatoid arthritis patients. When taken alone ˜12% ofpatients develop neutralizing antibodies. In addition, a smallpercentage of patients given the drug also contract a systemic lupuserthematosus-like condition that is an IgG-mediated immune responseinduced by the therapeutic agent (see Humira package label).

Another example of “deleterious immune response” is a host reaction tosmall molecule drugs. It is known to those skilled in the art thatcertain chemical structures will conjugate with host proteins tostimulate immune recognition (see Ju. C. et al. 2002. Current DrugMetabolism 3, pp 367-377 and Kimber I. et al. 2002, ToxicologicPathology 30, pp 54-58.) A substantial portion of these host reactionsare IgG mediated. Specific “deleterious immune responses” that are IgGmediated include: hemolytic anemia, Steven-Johnson syndrome and druginduced Lupus.

“Halo” refers to fluoro, chloro, bromo or iodo.

“Haloalkyl” refers to alkyl as defined above substituted by one or more,for example from one to thirteen, preferably from one to seven, “halo”atoms, as such terms are defined in this Application. Haloalkyl includesmonohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl and the like e.g.chloromethyl, dichloromethyl, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, perfluoroethyl, 2,2,2-trifluoro-1,1-dichloroethyl,and the like.

“Haloalkylene” means alkylene radical as defined above wherein one tofour, preferably one or two hydrogen atoms in the alkylene chainhas(have) been replaced by fluorine atom(s).

“Haloalkoxy” refers to a —OR radical where R is haloalkyl group asdefined above e.g., trifluoromethoxy, 2,2,2-trifluoroethoxy,difluoromethoxy, and the like.

“Heteroaryl” as a group or part of a group denotes an aromaticmonocyclic or bicyclic moiety of 5 to 10 ring atoms in which one ormore, preferably one, two, or three, of the ring atom(s) is(are)selected from nitrogen, oxygen or sulfur, the remaining ring atoms beingcarbon. Representative heteroaryl rings include, but are not limited to,pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, pyrazolyl, and the like.

“Heteroaryloxy” refers to a —O—R radical where R is heteroaryl asdefined above e.g., furanyloxy, pyridinyloxy, indolyloxy, and the like.

“Heteroaryloxycarbonyl” refers to a —C(O)O—R radical where R isheteroaryl as defined above e.g., pyridinyloxycarbonyl,pyrimidinyloxycarbonyl, and the like.

“Heteroaralkyl” refers to a -(alkylene)-R radical where R is heteroarylas defined above e.g., pyridinylmethyl, 1- or 2-furanylethyl,imidazolylmethyl, and the like.

“Heteroaralkyloxy” refers to a —O—R radical where R is heteroaralkyl asdefined above e.g., pyridinylmethyloxy, furanylethyloxy, and the like.

“Heteroaralkyloxycarbonyl” refers to a —C(O)O—R radical where R isheteroaralkyl as defined above e.g., pyridinylmethyloxycarbonyl,pyrimidinylmethyloxycarbonyl, and the like.

“Heterocycloalkyl” refers to a saturated or partially unsaturated, monoor bicyclic radical of 4, 5 or 6 carbon ring atoms wherein one or more,preferably one, two, or three of the ring carbon atoms are replaced by aheteroatom selected from —N═, —N—, —O—, —S—, —SO—, or —S(O)₂— andfurther wherein one or two ring carbon atoms are optionally replaced bya keto (—CO—) group. The heterocycloalkyl ring is optionally fused tocycloalkyl, aryl or heteroaryl ring as defined herein. Representativeexamples include, but are not limited to, imidazolidinyl, morpholinyl,thiomorpholinyl, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide,tetrahydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl,1-oxo-tetrahydrothiopyranyl, 1,1-dioxotetrathio-pyranyl, indolinyl,piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl,quinuclidinyl,3,4-dihydroisoquinolinyl, dihydroindolyl, and the like.

When the heterocycloalkyl group contains at least one nitrogen ring atomit is referred to herein as “heterocycloamino” and is a subset of theheterocycloalkyl group as defined above.

“Heterocyclylalkylene” refers to a divalent heterocyclyl group, asdefined in this Application, e.g., the instance wherein R³ and R⁴together with the carbon atom to which both R³ and R⁴ are attached formheterocyclylalkylene” includes, but is not limited to, the following:

in which R is a substituent defined in the Summary of the Invention

“Heterocycloalkylalkyl” refers to a -(alkylene)-R radical where R isheterocycloalkyl as defined above e.g., pyrrolidinylmethyl,tetrahydrofuranylethyl, pyridinylmethylpiperidinylmethyl, and the like.

“Heterocycloalkyloxycarbonyl” refers to a —C(O)OR radical where R isheterocycloalkyl as defined above e.g., pyridinyloxycarbonyl,pyrimidinyloxycarbonyl, and the like.

“Hydroxy” means —OH radical. Unless indicated otherwise, the compoundsof the invention containing hydroxy radicals include protectedderivatives thereof. Suitable protecting groups for hydroxy moietiesinclude benzyl and the like.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with one or two hydroxy groups, provided thatif two hydroxy groups are present they are not both on the same carbonatom. Representative examples include, but are not limited to,hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

“Isomers” mean compounds of Formula (I) having identical molecularformulae but differ in the nature or sequence of bonding of their atomsor in the arrangement of their atoms in space. Isomers that differ inthe arrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers”. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”. A compound with one chiral center that has two enantiomericforms of opposite chirality is termed a “racemic mixture”. A compoundthat has more than one chiral center has 2^(n−1) enantiomeric pairs,where n is the number of chiral centers. Compounds with more than onechiral center may exist as either an individual diastereomer or as amixture of diastereomers, termed a “diastereomeric mixture”. When onechiral center is present a stereoisomer may be characterized by theabsolute configuration of that chiral center. Absolute configurationrefers to the arrangement in space of the substituents attached to thechiral center. Enantiomers are characterized by the absoluteconfiguration of their chiral centers and described by the R- andS-sequencing rules of Cahn, Ingold and Prelog. Conventions forstereochemical nomenclature, methods for the determination ofstereochemistry and the separation of stereoisomers are well known inthe art (e.g., see “Advanced Organic Chemistry”, 4th edition, March,Jerry, John Wiley & Sons, New York, 1992). It is understood that thenames and illustration used in this Application to describe compounds ofFormula (I) are meant to be encompassed all possible stereoisomers.

“Optional” or “optionally” or “may be” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, the phrase “wherein thearomatic ring in R^(a) is optionally substituted with one or twosubstituents independently selected from alkyl” means that the aromaticring may or may not be substituted with alkyl in order to fall withinthe scope of the invention.

The present invention also includes N-oxide derivatives of a compound ofFormula (I). N-oxide derivative mean a compound of Formula (I) in whicha nitrogen atom is in an oxidized state (i.e., N→O) e.g., pyridineN-oxide, and which possess the desired pharmacological activity.

“Pathology” of a disease means the essential nature, causes anddevelopment of the disease as well as the structural and functionalchanges that result from the disease processes.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of Formula(I) which are pharmaceutically acceptable, as defined above, and whichpossess the desired pharmacological activity. Such salts include acidaddition salts formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or with organic acids such as acetic acid, propionic acid,hexanoic acid, heptanoic acid, cyclopentanepropionic acid, glycolicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, o-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methylsulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxy-ethanesulfonic acid, benzenesulfonic acid,p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

The present invention also includes prodrugs of a compound of Formula(I). Prodrug means a compound that is convertible in vivo by metabolicmeans (e.g. by hydrolysis) to a compound of Formula (I). For example, anester of a compound of Formula (I) containing a hydroxy group may beconvertible by hydrolysis in vivo to the parent molecule. Alternativelyan ester of a compound of Formula (I) containing a carboxy group may beconvertible by hydrolysis in vivo to the parent molecule. Suitableesters of compounds of Formula (I) containing a hydroxy group, are forexample acetates, citrates, lactates, tartrates, malonates, oxalates,salicylates, propionates, succinates, fumarates, maleates,methylene-bis-βb-hydroxynaphthoates, gentisates, isethionates,di-p-toluoyltartrates, methylsulphonates, ethanesulphonates,benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates andquinates. Suitable esters of compounds of Formula (I) containing acarboxy group, are for example those described by Leinweber, F. J. DrugMetab. Res., 1987, 18, page 379. An especially useful class of esters ofcompounds of Formula (I) containing a hydroxy group, may be formed fromacid moieties selected from those described by Bundgaard et al., J. Med.Chem., 1989, 32, pp 2503-2507, and include substituted(aminomethyl)-benzoates, for example, dialkylamino-methylbenzoates inwhich the two alkyl groups may be joined together and/or interrupted byan oxygen atom or by an optionally substituted nitrogen atom, e.g. analkylated nitrogen atom, more especially (morpholino-methyl)benzoates,e.g. 3- or 4-(morpholinomethyl)-benzoates, and(4-alkylpiperazin-1-yl)benzoates, e.g. 3- or4-(4-alkylpiperazin-1-yl)benzoates.

“Protected derivatives” means derivatives of compounds of Formula (I) inwhich a reactive site or sites are blocked with protecting groups.Protected derivatives of compounds of Formula (I) are useful in thepreparation of compounds of Formula (I) or in themselves may be activecathepsin S inhibitors. A comprehensive list of suitable protectinggroups can be found in T. W. Greene, Protective Groups in OrganicSynthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

-   (1) preventing the disease from occurring in an animal which may be    predisposed to the disease but does not yet experience or display    the pathology or symptomatology of the disease,-   (2) inhibiting the disease in an animal that is experiencing or    displaying the pathology or symptomatology of the diseased (i.e.,    arresting further development of the pathology and/or    symptomatology), or-   (3) ameliorating the disease in an animal that is experiencing or    displaying the pathology or symptomatology of the diseased (i.e.,    reversing the pathology and/or symptomatology).

“Treatment” or “treating” with respect to combination therapy i.e., usewith a biologic means any administration of a compound of the presentinvention and includes:

-   (1) preventing the immune response from occurring in an animal which    may be predisposed to the immune response but does not yet    experience or display the pathology or symptomatology of the immune    response,-   (2) inhibiting the immune response in an animal that is experiencing    or displaying the pathology or symptomatology of the immune response    (i.e., arresting further development of the pathology and/or    symptomatology), or-   (3) ameliorating the immune response in an animal that is    experiencing or displaying the pathology or symptomatology of the    immune response (i.e., reducing in degree or severity, or extent or    duration, the overt manifestations of the immune response or    reversing the pathology and/or symptomatology e.g., reduced binding    and presentation of antigenic peptides by MHC class II molecules,    reduced activation of T-cells and B-cells, reduced humoral and    cell-mediated responses and, as appropriate to the particular immune    response, reduced inflammation, congestion, pain, necrosis, reduced    loss in the efficacy of a biologic agent, and the like).

The expression “wherein the aromatic or alicyclic ring in R⁵ isoptionally substituted with one, two, or three R^(a) independentlyselected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo; oroptionally substituted with one or two R^(b) independently selected fromhydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy,or alkoxycarbonyl and one le selected from hydroxyalkyl, alkoxyalkyl,aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl,cycloalkylalkyl, . . . ” in the definition of R⁵ in the compound ofFormula (I) means that all the aromatic and alicyclic rings within thescope of R⁵ whether directly or indirectly attached (e.g., R⁵ iscycloalkylalkyl, -alkylene-X—R⁹ where X is as defined in the Summary ofthe Invention and R⁹ is ary, aralkyl, etc, . . . ) are optionallysubstituted with R^(a), or R^(b) and R^(c), or R^(c) alone.

Preferred Embodiments

I. Certain compounds of Formula (I) within the broadest scope set forthin the Summary of the Invention are preferred. For example:

-   (A) A preferred group of compounds is that wherein:

R¹ is hydrogen or methyl, preferably hydrogen;

R² is cyclopropyl, 1-phenylethyl[-CH(C₆H₅)CH₃], or 1H-pyrazol-5-yl;preferably cyclopropyl.

(1) Within the above preferred group (A) and more preferred groupcontained therein, a more preferred group of compounds is that whereinR³ is hydrogen and R⁴ is alkyl, preferably methyl, ethyl, propyl orbutyl, more preferably R⁴ is ethyl or propyl.

(2) Within the above preferred group (A) and more preferred groupcontained therein, a more preferred group of compounds is that whereinR³ is alkyl, preferably methyl or ethyl and R⁴ is alkyl, preferablymethyl, ethyl, propyl or butyl, more preferably R⁴ is methyl.Preferably, R³ and R⁴ are methyl.

(3) Within the above preferred group (A) and more preferred groupscontained therein, a more preferred group of compounds is that whereinR³ and R⁴ together with the carbon atom to which they are attached formcycloalkylene, preferably cyclopropylene, cyclopentylene, orcyclohexylene, more preferably cyclopropylene.

(4) Within the above preferred group (A) and more preferred groupcontained therein, a more preferred group of compounds is that whereinR³ and R⁴ together with the carbon atom to which they are attached formpiperidin-4-yl substituted at the nitrogen atom with ethyl,2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl,tetrahydrothiopyran-4-yl, or 1,1-dioxotetrahydrothiopyran-4-yl.

(i) Within the above preferred groups (A) and A(1-4) and more preferredgroups contained therein, a more preferred group of compounds is thatwherein R⁶ is haloalkyl, preferably, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl,1,1,2,2,3,3,3-heptafluoropropyl and R⁷ and R⁸ are hydrogen.

(ii) Within the above preferred groups (A) and A(1-4) and more preferredgroups contained therein, a more preferred group of compounds is thatwherein R⁶ is haloalkyl, preferably, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R⁷ is haloalkyl,preferably, trifluoromethyl, 2,2,2-trifluoroethyl, or1,1,2,2,2-pentafluoroethyl, and R⁸ is hydrogen.

(iii) Within the above preferred groups (A) and A(1-4) and morepreferred groups contained therein, a more preferred group of compoundsis that wherein R⁶ is haloalkyl, preferably, difluoromethyl,trifluoromethyl, 2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R⁷is alkyl, preferably, methyl, ethyl, or propyl, and R⁸ is hydrogen.

(iv) Within the above preferred groups (A) and A(1-4) and more preferredgroups contained therein, a more preferred group of compounds is thatwherein R⁶ is haloalkyl, preferably, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R⁷ is haloalkyl,preferably, trifluoromethyl or 2,2,2-trifluoroethyl, and R⁸ is aryloptionally substituted with one, two, or three R^(e). Preferably R⁸ isphenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or3,5-difluorophenyl. More preferably, R⁶ and R⁷ are trifluoromethyl andR⁸ is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4,- or3,5-difluorophenyl.

(iv) Within the above preferred groups (A) and A(1-4) and more preferredgroups contained therein, a more preferred group of compounds is thatwherein R⁶ is haloalkyl, preferably, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, or 1,1,2,2,3-pentafluoroethyl, R⁷ is alkyl,preferably, methyl or ethyl, and R⁸ is aryl optionally substituted withone, two, or three R^(e). Preferably R⁸ is phenyl, 4-fluorophenyl, 2,3-,2,4-, 2,5-, 2,6-, 3,4, or 3,5-difluorophenyl. More preferably, R⁶ istrifluoromethyl and R⁷ is methyl and R⁸ is phenyl, 4-fluorophenyl, 2,3-,2,4-, 2,5-, 2,6-, 3,4,- or 3,5-difluorophenyl.

(v) Within the above preferred groups (A) and A(1-4) and more preferredgroups contained therein, a more preferred group of compounds is thatwherein R⁶ is haloalkyl, preferably, trifluoromethyl, difluoromethyl,2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R⁷ is hydrogen, andR⁸ is aryl optionally substituted with one, two, or three R^(e).Preferably R⁸ is phenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4,-or 3,5-difluorophenyl. More preferably, R⁶ is trifluoromethyl and R⁸ isphenyl, 4-fluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4, or3,5-difluorophenyl, preferably 2,4-difluorophenyl.

(vi) Within the above preferred groups (A) and A(1-4) and more preferredgroups contained therein, a more preferred group of compounds is thatwherein R⁶ is haloalkyl, preferably, trifluromethyl,2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R⁷ is haloalkyl,preferably, trifluoromethyl or 2,2,2-trifluoroethyl, and R⁸ isheteroaryl optionally substituted with one, two, or three R^(e).Preferably R⁸ is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl,thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl,imidazol-5-yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl,pyrimdin-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl,[1.2.3]thiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl,pyrazol-4-yl, pyrrol-3-yl, thiazol-4-yl, thiazol-5-yl optionallysubstituted with one or two methyl.

(vii) Within the above preferred groups (A) and A(1-4) and morepreferred groups contained therein, a more preferred group of compoundsis that wherein R⁶ is haloalkyl, preferably, trifluromethyl,2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R⁷ is alkyl,preferably, methyl or ethyl, and and R⁸ is heteroaryl optionallysubstituted with one, two, or three R^(e). Preferably R⁸ is indol-5-yl,benzoxazol-5-yl, thiophen-3-yl, thiophen-2-yl, furan-2-yl,pyridine-4-yl, pyridin-3-yl, pyridin-2-yl, imidazol-5-yl,pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl, pyrimdin-4-yl,pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl, [1.2.3]thiadiazol-4-yl,imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl, pyrazol-4-yl, pyrrol-2-yl,pyrrol-3-yl, thiazol-4-yl, thiazol-5-yl optionally substituted with oneor two methyl.

(viii) Within the above preferred groups (A) and A(1-4) and morepreferred groups contained therein, a more preferred group of compoundsis that wherein R⁶ is haloalkyl, preferably, trifluromethyl,2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R⁷ is hydrogen, andand R⁸ is heteroaryl optionally substituted with one, two, or threeR^(e). Preferably R⁸ is indol-5-yl, benzoxazol-5-yl, thiophen-3-yl,thiophen-2-yl, furan-2-yl, pyridin-4-yl, pyridin-3-yl, pyridin-2-yl,imidazol-5-yl, pyrimidin-2-yl, pyrazin-2-yl, pyrimidin-5-yl,pyrimdin-4-yl, pyridazin-4-yl, isoxazol-4-yl, imidazol-2-yl,[1.2.3]thiadiazol-4-yl, imidazol-4-yl, pyrazol-4-yl, thiazol-2-yl,pyrazol-4-yl, pyrrol-2-yl, pyrrol-3-yl, thiazol-4-yl, thiazol-5-yloptionally substituted with one or two methyl.

(a) Within the above preferred groups (A), A(1-4), A(i-viii) andA(1-4)(i-viii), and more preferred groups contained therein, an evenmore preferred group of compounds is that wherein R⁵ is cycloalkylalkyloptionally substituted with one, two, or three R^(a) independentlyselected from alkyl or halo or an R^(e) selected from aralkyl orheteroaralkyl, preferably 1-methylcyclopentylmethyl,1-methylcyclohexylmethyl, 1-methylcyclobutylmethyl,1-methyl-3,3-difluorocyclobutylmethyl,1-methyl-4,4-difluorocyclohexylmethyl, 1-benzyl-cyclopropylmethyl,1-thiazol-2-ylmethylcyclopropylmethyl, or1-methyl-3,3-difluorocyclopentylmethyl.

(b) Within the above preferred groups (A), A(1-4), A(1-viii) andA(i-4)(i-viii), and more preferred groups contained therein, an evenmore preferred group of compounds is that wherein R⁵ is alkyl,preferably 2,2-dimethylpropyl, 3,3-dimethylpentyl,2,2,3,3-tetramethylbutyl.

(c) Within the above preferred groups (A), A(1-4), A(1-viii) andA(i-4)(i-viii), and more preferred groups contained therein, an evenmore preferred group of compounds is that wherein R⁵ is haloalkyl,preferably 2,2-dichloroethyl, 3,3,3-trifluoropropyl,2,2-trifluoromethylethyl, or 2,2,2-trifluoroethyl.

(d) Within the above preferred groups (A), A(1-4), A(i-viii) andA(1-4)(i-viii), and more preferred groups contained therein, an evenmore preferred group of compounds is that wherein R⁵ is haloalkylsubstituted with aryl, heteroaryl or heterocycloalkyl, preferably2,2-difluoro-3-phenylpropyl, 2,2-difluoro-3-tetrahydropyran-4-ylpropyl,2,2-difluoro-3-morpholin-4-ylpropyl, 2,2-difluoro-3-pyridin-2-ylpropyl,2,2-difluoro-3-pyridin-3-ylpropyl, or 2,2-dichloro-3-phenylpropyl.

(e) Within the above preferred groups (A), A(1-4), A(i-viii) andA(1-4)(i-viii), and more preferred groups contained therein, an evenmore preferred group of compounds is that wherein R⁵ is aralkyloptionally substituted with one, two, or three R^(a) independentlyselected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, orhalo; or optionally substituted with one or two R^(b) independentlyselected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy,halo, carboxy, or alkoxycarbonyl and one R^(c) selected fromhydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, acyl, aryloxycarbonyl, aralkyloxycarbonyl,heteroaryloxycarbonyl, heteroaralkyloxycarbonyl,heterocycloalkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aminocarbonyl, aminosulfonyl, or —SO₂R¹¹ (where R¹¹ isalkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl); and furtherwherein the aromatic or alicyclic ring in R^(c) is optionallysubstituted with one, two, or three R^(d) independently selected fromalkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo. Preferably, R⁵is benzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, 2-chlorobenzyl,4-ethoxybenzyl, biphen-4-ylmethyl, naphth-1-ylmethyl, naphth-2-ylmethyl,4-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 2-phenethyl,4-hydroxybenzyl, 2-(4-hydroxyphenyl)ethyl, 2,6-difluorobenzyl,biphenyl-3-ylmethyl, 3-phenylpropyl, or 2,2-dimethyl-3-phenylpropyl.Preferably, R⁵ is 2-chlorobenzyl, 3-chlorobenzyl, or 4-fluorobenzyl.

(f) Within the above preferred groups (A), A(1-4), A(i-viii) andA(1-4)(i-viii), and more preferred groups contained therein, an evenmore preferred group of compounds is that wherein R⁵ is heteroaralkyloptionally substituted with one, two, or three R^(a) independentlyselected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, orhalo; or optionally substituted with one or two R^(b) independentlyselected from hydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy,halo, carboxy, or alkoxycarbonyl and one R^(c) selected fromhydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, acyl, aryloxycarbonyl, aralkyloxycarbonyl,heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, aryloxy, heteroaryloxy,aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl, or —SO₂R¹¹(where R¹¹ is alkyl, aryl, heteroaryl, or heterocycloalkyl); and furtherwherein the aromatic or alicyclic ring in R^(c) is optionallysubstituted with one, two, or three R^(d) independently selected fromalkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo. Preferably, R⁵is 2-bromothiophen-5-ylmethyl, pyridin-4-ylmethyl, or2,2-dimethyl-3-pyridin-3-ylpropyl.

(g) Within the above preferred groups (A), A(1-4), A(i-viii) andA(1-4)(i-viii), and more preferred groups contained therein, an evenmore preferred group of compounds is that wherein R⁵ is-(alkylene)-S(O)₂—R⁹ where R⁹ is alkyl, preferably R⁵ ismethylsulfonylmethyl, ethylsulfonylmethyl, propyl-1-sulfonylmethyl,2-methylpropylsulfonylmethyl, 2-methyl-sulfonylethyl, or2-ethylsulfonylethyl.

(h) Within the above preferred groups (A), A(1-4), A(i-viii) andA(1-4)(i-viii), and more preferred groups contained therein, an evenmore preferred group of compounds is that wherein R⁵ is-(alkylene)-S(O)₂—R⁹ where R⁹ is aryl or aralkyl optionally substitutedwith one, two, or three R⁵ independently selected from alkyl, haloalkyl,alkoxy, hydroxy, haloalkoxy, cyano, or halo; or optionally substitutedwith one or two R^(b) independently selected from hydrogen, alkyl,haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyland one R^(c) selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, acyl, aryloxycarbonyl,aralkyloxycarbonyl, heteroaryloxycarbonyl, heteroaralkyloxycarbonyl,aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aminocarbonyl,aminosulfonyl, or —SO₂R¹¹ (where R¹¹ is alkyl, aryl, heteroaryl, orheterocycloalkyl); and further wherein the aromatic or alicyclic ring inR^(c) is optionally substituted with one, two, or three R^(d)independently selected from alkyl, haloalkyl, alkoxy, hydroxy,haloalkoxy, or halo. Preferably R⁵ is2-difluoromethoxyphenylmethanesulfonylmethyl, 2-phenylsulfonylethyl,4-fluorophenylmethanesulfonylmethyl,4-aminocarbonylphenylmethanesulfonylmethyl,4-piperazin-1-ylphenylmethanesulfonylmethyl,2-fluorophenylmethanesulfonylmethyl,3-fluorophenylmethanesulfonylmethyl,2,4,6-trifluorophenylmethanesulfonylmethyl, 2-, 3-, or4-trifluoromethylphenylmethanesulfonylmethyl,phenylmethanesulfonylmethyl, 2-(2-, 3-, or4-trifluoromethylphenyl)sulfonylethyl, or 2-(2-, 3-, or4-fluorophenyl)sulfonylethyl.

(i) Within the above preferred groups (A), A(1-4), A(i-viii) andA(1-4)(i-viii), and more preferred groups contained therein, an evenmore preferred group of compounds is that wherein R⁵ is-(alkylene)-S(O)₂—R⁹ where R⁹ is heteroaryl or heteroaralkyl optionallysubstituted with one, two, or three R^(a) independently selected fromalkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, or halo; oroptionally substituted with one or two R^(b) independently selected fromhydrogen, alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halo, carboxy,or alkoxycarbonyl and one R^(c) selected from hydroxyalkyl, alkoxyalkyl,aminoalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, acyl,aryloxycarbonyl, aralkyloxycarbonyl, heteroaryloxycarbonyl,heteroaralkyloxycarbonyl, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aminocarbonyl, aminosulfonyl, or —SO₂R¹¹ (where R¹¹ isalkyl, aryl, heteroaryl, or heterocycloalkyl); and further wherein thearomatic or alicyclic ring in R^(c) is optionally substituted with one,two, or three R^(d) independently selected from alkyl, haloalkyl,alkoxy, hydroxy, haloalkoxy, or halo. Preferably R⁵ ispyridin-2-_(y)lmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl,pyridin-4-ylmethanesulfonylmethyl,3-difluoromethoxypyridin-2-ylmethanesulfonylmethyl,2-difluoromethoxypyridin-3-ylmethanesulfonylmethyl,4-difluoromethoxypyridin-3-ylmethanesulfonylmethyl,3-difluoromethoxypyridin-4-ylmethanesulfonylmethyl,pyrimidin-2-ylmethanesulfonylmethyl,pyrimidin-5-ylmethanesulfonylmethyl,3-trifluoromethylpyridin-2-ylmethanesulfonylmethyl,4-trifluoromethylpyridin-3-ylmethanesulfonylmethyl,3,5-dimethylisoxazol-4-ylmethanesulfonylmethyl,2-fluorofuran-5-ylmethanesulfonyhnethyl,2-methylthiazol-4-ylmethanesulfonylmethyl,furan-2-ylmethanesulfonylmethyl, 2-pyridin-2-ylethanesulfonylmethyl,2-pyridin-3-ylethanesulfonylmethyl, 2-pyridin-4-ylethanesulfonylmethyl,2-pyridin-3-ylsulfonylethyl, 2-pyridin-4-ylsulfonylethyl,3-pyridin-3-ylsulfonylpropyl, 1,3,5-triazin-2-ylmethanesulfonylmethyl,1,3,4-thiadiazol-2-ylmethanesulfonylmethyl,oxazol-5-ylmethanesulfonylmethyl, thiazol-5-ylmethanesulfonylmethyl, orthiazol-2-ylmethanesulfonylmethyl.

(j) Within the above preferred groups (A), A(1-4), A(i-viii) andA(1-4)(i-viii), and more preferred groups contained therein, an evenmore preferred group of compounds is that wherein R⁵ is-(alkylene)-S(O)₂—R⁹ where R⁹ is heterocycloalkyl orheterocycloalkylalkyl optionally substituted with one, two, or threeR^(a) independently selected from alkyl, haloalkyl, alkoxy, hydroxy,haloalkoxy, cyano, or halo; or optionally substituted with one or twoR^(b) independently selected from hydrogen, alkyl, haloalkyl, alkoxy,hydroxy, haloalkoxy, halo, carboxy, or alkoxycarbonyl and one R^(c)selected from hydroxyalkyl, alkoxyalkyl, aminoalkyl, aryl, heteroaryl,aralkyl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, acyl, aryloxycarbonyl, aralkyloxycarbonyl,heteroaryloxycarbonyl, heteroaralkyloxycarbonyl, aryloxy, heteroaryloxy,aralkyloxy, heteroaralkyloxy, aminocarbonyl, aminosulfonyl, or —SO₂R¹¹(where R¹¹ is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl);and further wherein the aromatic or alicyclic ring in is optionallysubstituted with one, two, or three R^(d) independently selected fromalkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, or halo. Preferably, R⁵is piperidin-1-ylsulfonylmethyl or piperidin-4-ylmethanesulfonylmethylwherein the nitrogen atom in the piperidine ring is substituted withmethyl, ethyl, acetyl, methylsulfonyl, or aminosulfonyl,tetrahydropyran-4-ylsulfonylmethyl, tetrahydropyran-4-ylsulfonylmethyl,1,1-dioxotetrahydrothiopyran-4-ylmethanesulfonylmethyl, ormorpholin-4-ylmethanesulfonyl-methyl.

(k) Within the above preferred groups (A), A(1-4), A(i-viii) andA(1-4)(i-viii), and more preferred groups contained therein, an evenmore preferred group of compounds is that wherein R⁵ is-(alkylene)-S(O)₂—R⁹ where R⁹ is cycloalkylalkyl, preferably R⁵ iscyclopropylmethylsulfonylmethyl.

(l) Within the above preferred groups (A), A(1-4), A(i-viii) andA(1-4)(i-viii), and more preferred groups contained therein, R⁵ isethylsulfonylmethyl, 2-methysulfonylethyl, 2-methylpropylsulfonylmethyl,benzenesulfonylmethyl, 2-phenylsulfonylethyl,naphth-2-ylmethanesulfonylmethyl, biphenyl-2-ylmethanesulfonylmethyl,biphenyl-4-ylmethanesulfonylmethyl, phenylmethanesulfonylmethyl,2-phenylmethanesulfonylethyl, 4-tert-butylphenylmethanesulfonylmethyl,2-fluoro-phenylmethanesulfonylmethyl,3-fluorophenylmethane-sulfonylmethyl,4-fluorophenylmethanesulfonylmethyl,2-chlorophenylmethanesulfonylmethyl,3-chlorophenylmethanesulfonylmethyl,4-chlorophenylmethanesulfonylmethyl,2-methoxyphenylmethanesulfonylmethyl,4-methoxyphenylmethanesulfonylmethyl,2-trifluoromethoxyphenylmethanesulfonylmethyl,3-trifluoromethoxyphenylmethanesulfonyl-methyl,4-trifluoromethoxyphenylmethanesulfonylmethyl,2-trifluoromethylphenyl-methanesulfonylmethyl,3-trifluoromethylphenylmethanesulfonylmethyl,4-trifluoromethylphenylmethanesulfonylmethyl,2-cyanophenylmethanesulfonylmethyl, 3-cyanophenyhnethanesulfonylmethyl,2-bromophenylmethanesulfonyhnethyl, 2-methylphenylmethanesulfonylmethyl,3-methylphenylmethanesulfonylmethyl,4-methyiphenylmethanesulfonylmethyl,2-(4-trifluoromethoxy-benzenesulfonyl)ethyl,2-(3-trifluoromethoxybenzenesulfonyl)ethyl,2-(2-trifluoromethoxybenzenesulfonyl)-ethyl,2-difluoromethoxyphenylmethanesulfonylmethyl,3-difluoromethoxyphenylmethanesulfonylmethyl,4-difluoromethoxyphenylmethanesulfonylmethyl,2-(4-difluoromethoxybenzenesulfonyl)ethyl,2-(2-difluoromethoxybenzenesulfonyl)ethyl,2-(3-difluoromethoxybenzenesulfonyl)ethyl,3-chloro-2-fluorophenylmethanesulfonylmethyl,3,5-dimethylphenylmethanesulfonylmethyl,3,5-bis-trifluoromethylphenylmethanesulfonylmethyl,2,5-difluorophenylmethanesulfonylmethyl,2,6-difluorophenylmethanesulfonylmethyl,2,3-difluorophenylmethanesulfonylmethyl,3,4-difluorophenylmethanesulfonylmethyl,2,4-difluorophenylmethanesulfonylmethyl,2,5-dichlorophenylmethanesulfonylmethyl,3,4-dichlorophenylmethanesulfonylmethyl,2,6-dichlorophenylmethanesulfonylmethyl,2-fluoro-3-methylphenylmethanesulfonylmethyl,4-fluoro-2-trifluoromethoxyphenylmethanesulfonylmethyl,2-fluoro-6-trifluoromethylphenylmethanesulfonylmethyl,2-fluoro-3-trifluoromethylphenylmethanesulfonylmethyl,2-fluoro-4-trifluoromethylphenylmethanesulfonylmethyl,2-fluoro-5-trifluoromethylphenylmethanesulfonylmethyl,4-fluoro-3-trifluoromethylphenylmethanesulfonylmethyl,2-chloro-5-trifluoromethylphenylmethanesulfonylmethyl,2,4,6-trifluorophenylmethanesulfonylmethyl,2,4,5-trifluorophenylmethanesulfonylmethyl,2,3,4-trifluorophenylmethanesulfonylmethyl,2,3,5-trifluorophenylmethanesulfonylmethyl,2,5,6-trifluorophenylmethanesulfonyl-methyl,3,4,5-trimethoxyphenylmethanesulfonylmethyl,pyridin-2-ylmethanesulfonylmethyl, pyridin-3-ylmethanesulfonylmethyl,pyridin-4-yl-methanesulfonylmethyl, 2-(pyridin-2-ylsulfonyl)ethyl,2-(pyridin-4-ylsulfonyl)ethyl, oxypyridin-2-ylmethanesulfonylmethyl,cyclohexylmethanesulfanylmethyl, cyclohexylmethanesulfonylmethyl,cyclopropylmethanesulfonylmethyl, thiophene-2-sulfonylmethyl,5-chlorothien-2-ylmethanesulfonylmethyl, or3,5-dimethylisoxazol-4-ylmethanesulfonylmethyl.

(m) Within the above preferred groups (A), A(1-4), A(i-viii) andA(1-4)(i-viii), and more preferred groups contained therein, R⁵ is1-ethoxycarbonylpiperidin-4-ylmethyl, 1-methylpiperidin-4-ylmethyl,2-tetrahydropyran-4-ylethyl, pyrrolidin-1-ylmethyl,piperidin-1-ylmethyl, morpholin-4-ylmethyl, 2-morpholin-4-ylethyl,thiomorpholin-4-ylmethyl, 1-oxothiomorpholin-4-ylmethyl,1,1-dioxothiomorpholin-4-ylmethyl, tetrahydrothiopyran-4-ylmethyl,1-oxotetrahydrothiopyran-4-ylmethyl,1,1-dioxotetrahydrothiopyran-4-ylmethyl, 1-methylpiperazin-4-ylmethyl,benzyloxymethyl, ethoxymethyl, isopropyloxymethyl,2-piperidin-1-yl-ethyl, 2-pyrrolidin-1-ylethyl, tert-butyloxymethyl,imidazol-4-ylmethyl, indol-3-ylmethyl, indol-2-ylmethyl,1-benzyl-imidazol-4-ylmethyl, 4-ethyl-4-methylpiperidin-1-ylmethyl,indol-1-ylmethyl, 1-methyl-piperidin-2-ylmethyl,2,2,-difluoro-3-thien-2-ylmethyl, or pyridin-4-ylmethyl.

(n) Within the above preferred groups (A), A(1-4), A(i-viii) andA(1-4)(i-viii), and more preferred groups contained therein, R⁵ is3,5-dimethylisoxazol-4-ylmethanesulfonylmethyl;2-CF₃methylphenylmethane-sulfonylmethyl,3-CF₃pyridin-2-ylmethanesulfonylmethyl,2-F-furan-5-ylmethanesulfonyl-methyl,2-methylthiazol-4-ylmethanesulfonylmethyl,tetrahydropyran-4-ylmethane-sulfonylmethyl,1,1-dioxo-1λ⁶-hexahydrothiopyran-4-ylmethanesulfonylmethyl,1-ethylpiperidin-4-ylmethanesulfonylmethyl,2-oxo-tetrahydropyrimidin-4-ylmethane-sulfonylmethyl,1-ethyl-2-oxopiperidin-4-ylmethanesulfonylmethyl,1-acetylpiperidin-4-ylmethanesulfonylmethyl,1-ethoxycarbonylpiperidin-4-ylmethanesulfonylmethyl,1-methylsulfonylpiperidin-4-ylmethanesulfonylmethyl,1-cyclopropylpiperidin-4-ylmethane-sulfonylmethyl,1-acetylazetidin-3-ylmethanesulfonylmethyl,1-ethoxycarbonylazetidin-3-ylmethanesulfonylmethyl,1-methylsulfonylazetidin-3-ylmethanesulfonylmethyl,1-ethylazetidin-3-ylmethanesulfonylmethyl,1-cyclopropylazetidin-3-ylmethanesulfonylmethylfuran-2-ylmethanesulfonylmethyl,difluoro-(4-fluorophenyl)methanesulfonylmethyl,difluoro-(pyrazin-2-yl)methanesulfonylmethyl,difluoro-(2-difluoromethoxyphenyl)methanesulfonylmethyl,1-acetylpiperidin-4-ylsulfonylmethyl,1-ethoxycarbonylpiperidin-4-ylsulfonylmethyl,1-cyclopropyllpiperidin-4-ylsulfonylmethyl,2-(pyridin-2-yl)ethanesulfonyl-methyl,2-(pyridin-3-yl)ethanesulfonylmethyl,2-(pyridin-4-yl)ethanesulfonylmethyl,3-(pyridin-2-yl)propanesulfonylmethyl,2,6-difluorophenylmethanesulfonyl,[1.3.5]triazin-2-ylmethanesulfonylmethyl,[1.3.4]thiadiazol-2-ylmethanesulfonylmethyl,oxazol-5-ylmethane-sulfonylmethyl, thiazol-5-ylmethanesulfonyhnethyl,4-fluorophenylmethanesulfonylmethyl,4-aminocarbonylphenylmethanesulfonylmethyl,4-piperazin-4-ylphenylmethanesulfonylmethyl,5-fluoroindol-3-ylmethanesulfonylmethyl,4,6-difluoroindol-3-ylmethanesulfonylmethyl,1-methylindol-3-ylmethanesulfonylmethyl,4-fluoroindol-3-ylmethanesulfonylmethyl,2-(5-fluoroindol-3-yl)ethanesulfonylmethyl,2-(4,6-difluoroindol-3-yl)ethanesulfonylmethyl,2-(1-methylindol-3-yl)ethanesulfonylmethyl,2-(4-fluoroindol-3-yl)ethanesulfonylmethyl,2-quinolin-3-ylethanesulfonylmethyl,2-quinolin-2-ylethanesulfonylmethyl,isoquinolin-3-ylmethane-sulfonylmethyl,2-(isoquinolin-3-yl)ethanesulfonylmethyl,2,4-difluoropyridin-3-ylmethane-sulfonylmethyl,3,4-difluoropyridin-4-ylmethanesulfonylmethyl,difluoropyridin-3-yl)ethanesulfonylmethyl,2-(3,4-difluoropyridin-4-yl)ethanesulfonylmethyl,fluoro-(2,4-difluoropyridin-3-yl)methanesulfonylmethyl,fluoro-(3,4-difluoropyridin-4-yl)methane-sulfonylmethyl,2,4-diCF₃pyridin-3-ylmethanesulfonylmethyl,3,4-diCF₃pyridin-4-ylmethane-sulfonylmethyl,2-(2,4-diCF₃pyridin-3-yl)ethanesulfonylmethyl,diCF₃pyridin-4-yl)ethanesulfonylmethyl,fluoro-(2,4-diCF₃pyridin-3-yl)methanesulfonylmethyl,fluoro-(3,4-diCF₃pyridin-4-yl)methanesulfonylmethyl,4-F-pyridin-3-ylmethanesulfonylmethyl,3-F-pyridin-5-ylmethanesulfonylmethyl,2-F-pyridin-5-ylmethanesulfonylmethyl,2-F-pyridin-3-ylmethanesulfonylmethyl,5-F-pyridin-2-ylmethanesulfonylmethyl,4-F-pyridin-2-ylmethane-sulfonylmethyl,4-F-1-oxopyridin-3-ylmethanesulfonylmethyl,3-F-1-oxopyridin-5-ylmethane-sulfonylmethyl,2-F-1-oxopyridin-5-ylmethanesulfonylmethyl,2-F-1-oxopyridin-3-ylmethane-sulfonylmethyl,5-F-1-oxopyridin-2-ylmethanesulfonylmethyl,4-F-1-oxopyridin-2-ylmethane-sulfonylmethyl,4-CF₃-pyridin-2-ylmethanesulfonylmethyl,3-CF₃-pyridin-5-ylmethane-sulfonylmethyl,3-F-pyridin-2-ylmethanesulfonylmethyl,2-CF₃-pyridin-3-ylmethane-sulfonylmethyl,4-CF₃-1-oxopyridin-2-ylmethanesulfonylmethyl,3-CF₃-1-oxopyridin-5-ylmethanesulfonylmethyl,3-F-1-oxopyridin-2-ylmethanesulfonylmethyl,2-CF₃-1-oxopyridin-3-ylmethanesulfonylmethyl,5-CF₃-1-oxopyridin-2-ylmethanesulfonylmethyl,2-CH₃-pyridin-6-ylmethanesulfonylmethyl,3-CH₃-pyridin-2-ylmethanesulfonylmethyl,4-CH₃-pyridin-3-ylmethanesulfonylmethyl,3-CH₃-pyridin-4-ylmethanesulfonylmethyl,2-(2-CH₃-pyridin-6-yl)ethanesulfonylmethyl,2-(3-CF₃-pyridin-2-yl)ethanesulfonylmethyl,2-(4-CF₃-pyridin-3-yl)ethanesulfonylmethyl,2-(3-CF₃-pyridin-4-yl)ethanesulfonylmethyl,2-C₂H₅-pyridin-6-ylmethanesulfonylmethyl,3-C₂H₅-pyridin-2-ylmethanesulfonylmethyl,4-C₂H₅-pyridin-3-ylmethanesulfonylmethyl,3-C₂H₅-pyridin-4-ylmethanesulfonylmethyl,2-(2-C₂H₅-pyridin-6-yl)ethanesulfonylmethyl,2-(3-C₂H₅-pyridin-2-yl)ethanesulfonylmethyl,2-(4-C₂H₅-pyridin-3-yl)ethanesulfonylmethyl,2-(3-C₂H₅-pyridin-4-yl)ethanesulfonylmethyl,2-(2-CH₃-pyridin-3-yl)ethanesulfonylmethyl,2-CF₃-pyridin-3-ylmethanesulfonylmethyl,2-(3-CF₃-pyridin-4-yl)ethanesulfonylmethyl,3-CF₃-pyridin-4-ylmethanesulfonylmethyl,cinnolin-3-ylmethane-sulfonylmethyl,2-(cinnolin-3-yl)ethanesulfonylmethyl,phthalazin-1-ylmethanesulfonylmethyl,2-(phthalazin-1-yl)ethanesulfonylmethyl,2-(quinoxalin-2-yl)ethanesulfonylmethyl,quinazolin-2-ylmethanesulfonylmethyl,2-(quinazolin-2-yl)ethanesulfonylmethyl,[1,8]naphthyridin-2-ylmethanesulfonylmethyl,2-([1,8]naphthyridin-2-yl)ethanesulfonylmethyl,[1,8]naphthyridin-3-ylmethanesulfonylmethyl,2-([1,8]naphthyridin-3-yl)ethanesulfonylmethyl,3-Cl-pyridin-2-ylmethanesulfonylmethyl,4-Cl-pyridin-3-ylmethanesulfonylmethyl,3-Cl-pyridin-4-ylmethane-sulfonylmethyl,3-F-pyridin-2-ylmethanesulfonylmethyl,4-F-pyridin-3-ylmethanesulfonyl-methyl,3-F-pyridin-4-ylmethanesulfonylmethyl,isoquinolin-4-ylmethanesulfonylmethyl,6-phenylpyridin-2-ylmethanesulfonylmethyl,3-phenylpyridin-2-ylmethanesulfonylmethyl,4-phenylpyridin-3-ylmethanesulfonylmethyl,3-phenylpyridin-4-ylmethanesulfonylmethyl,2-(6-phenylpyridin-2-yl)ethanesulfonylmethyl,2-(3-phenylpyridin-2-yl)ethanesulfonylmethyl,2-(4-phenylpyridin-3-yl)ethanesulfonylmethyl,2-(3-phenylpyridin-4-yl)ethanesulfonylmethyl,6-(pyridin-2-yl)pyridin-2-ylmethanesulfonylmethyl,3-(pyridin-2-yl)pyridin-2-ylmethanesulfonylmethyl,4-(pyridin-2-yl)pyridin-3-ylmethanesulfonylmethyl,3-(pyridin-2-yl)pyridin-4-ylmethanesulfonylmethyl,2-[6-(pyridin-2-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[3-(pyridin-2-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[4-(pyridin-2-yl)pyridin-3-yl]ethanesulfonylmethyl,2-[3-(pyridin-2-yl)pyridin-4-yl]ethanesulfonylmethyl,6-(pyridin-3-yl)pyridin-2-ylmethane-sulfonylmethyl,3-(pyridin-3-yl)pyridin-2-ylmethanesulfonylmethyl,4-(pyridin-3-yl)pyridin-3-ylmethanesulfonylmethyl,3-(pyridin-3-yl)pyridin-4-ylmethanesulfonylmethyl,2-[6-(pyridin-3-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[3-(pyridin-3-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[4-(pyridin-3-yl)pyridin-3-yl]ethanesulfonylmethyl,2-[3-(pyridin-3-yl)pyridin-4-yl]ethanesulfonylmethyl,6-(pyridin-4-yl)pyridin-2-ylmethanesulfonylmethyl,3-(pyridin-4-yl)pyridin-2-ylmethanesulfonylmethyl,4-(pyridin-4-yl)pyridin-3-ylmethanesulfonylmethyl,3-(pyridin-4-yl)pyridin-4-ylmethanesulfonylmethyl,2-[6-(pyridin-4-yl)pyridin-2-yl]-ethanesulfonylmethyl,2-[3-(pyridin-4-yl)pyridin-2-yl]ethanesulfonylmethyl,2-[4-(pyridin-4-yl)pyridin-3-yl]ethanesulfonylmethyl,2-[3-(pyridin-4-yl)pyridin-4-yl]ethanesulfonylmethyl,2,2-dimethylcyclopropylmethanesulfonylmethyl,biphen-2-ylmethanesulfonylmethyl,2-thiophen-2-ylphenylmethanesulfonylmethyl,2-thiazol-2-ylphenylmethanesulfonylmethyl,2-thiazol-5-ylphenylmethanesulfonylmethyl,2-[1.2.3]thiadiazol-5-ylphenylmethanesulfonylmethyl,2-isoxazol-5-ylphenylmethanesulfonylmethyl,2-(1-methylpyrazol-5-yl)phenyl-methanesulfonylmethyl,2-[1.2.3]triazol-5-ylphenylmethanesulfonylmethyl,2-[1.2.3]oxadiazol-5-ylphenylmethanesulfonylmethyl,2-[(1.2.3)triazol-5-yl]phenylmethanesulfonylmethyl,2-[(1.2.3)triazol-1-yl]phenylmethanesulfonylmethyl,oxazolo[5,4-b]pyridin-2-ylmethane-sulfonylmethyl,oxazolo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,oxazolo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,benzimidazol-5-ylmethanesulfonylmethyl,benzimidazol-4-ylmethanesulfonylmethyl,3H-imidazo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,3H-imidazo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,3-CF₃-3H-imidazo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,3-CF₃-3H-imidazo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,1-CF₃-1H-imidazo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,1-CF₃-1H-imidazo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,thiazolo[5,4-b]pyridin-2-ylmethanesulfonylmethyl,thiazolo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,thiazolo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,5-CF₃thiazolo[5,4-b]pyridin-2-ylmethanesulfonylmethyl,4-CF₃-thiazolo[4,5-c]pyridin-2-ylmethanesulfonylmethyl,7-CF₃-thiazolo[4,5-b]pyridin-2-ylmethanesulfonylmethyl,3-CF₃-1H-pyrrolo[2,3-b]pyridin-2-ylmethanesulfonylmethyl,3-CF₃-1H-pyrrolo[3,2-c]pyridin-2-ylmethanesulfonylmethyl,3-CF₃-1H-pyrrolo[3,2-b]pyridin-2-ylmethanesulfonylmethyl,imidazo[1,2-c]pyrimidin-2-methanesulfonylmethyl,8-CF₃-imidazo[1,2-c]pyrimidin-2-methanesulfonylmethyl,imidazo[1,2-a]pyrimidin-2-methanesulfonylmethyl,8-CF₃-imidazo[1,2-b]pyridazin-2-ylmethanesulfonylmethyl,imidazo[1,2-a]pyrazin-2-methanesulfonylmethyl,8-CF₃-imidazo[1,2-a]pyrazin-2-methanesulfonylmethyl,pyrazolo[1,5-c]pyrimidin-2-ylmethanesulfonylmethyl,3-CF₃-pyrazolo[1,5-c]pyrimidin-2-ylmethanesulfonylmethyl,4-CF₃-pyrazolo[1,5-c]pyrimidin-2-ylmethanesulfonylmethyl,imidazo[1,2-d][1,2,4]triazin-2-methanesulfonylmethyl,3-CF₃-imidazo[1,2-d][1,2,4]triazin-2-methanesulfonylmethyl,[1,3]benzoxazol-2-ylmethanesulfonylmethyl,5-F-[1,3]benzoxazol-2-ylmethanesulfonylmethyl[1,3]benzoxazol-4-ylmethanesulfonylmethyl,2-CF₃-[1,3]benzoxazol-4-ylmethanesulfonyl-methyl,[1,3]benzoxazol-7-ylmethanesulfonylmethyl,2-CF₃-[1,3]benzoxazol-7-ylmethane-sulfonylmethyl,[1,2]benzoxazol-3-ylmethanesulfonylmethyl,[1,2]benzoxazol-4-ylmethanesulfonylmethyl,5-CF₃-[1,2]benzoxazol-4-ylmethanesulfonylmethyl,3-CF₃-[1,2]benzoxazol-4-ylmethanesulfonylmethyl,6-CF₃-[1,2]benzoxazol-7-ylmethane-sulfonylmethyl,6-CN-[1,2]benzoxazol-7-ylmethanesulfonylmethyl,3-CF₃-[1,2]benzoxazol-7-ylmethanesulfonylmethyl,5-F-[1,2]benzoxazol-3-ylmethanesulfonylmethyl,[2,3]benzoxazol-7-ylmethanesulfonylmethyl,6-CF₃-[2,3]benzoxazol-7-ylmethanesulfonylmethyl,1-CF₃-[2,3]benzoxazol-7-ylmethanesulfonylmethyl,5-CF₃-[2,3]benzoxazol-4-ylmethanesulfonylmethyl,5-CN-[2,3]benzoxazol-4-ylmethanesulfonylmethyl,1-CF₃-[2,3]benzoxazol-4-ylmethanesulfonylmethyl,benzothiazol-2-ylmethanesulfonylmethyl,5-F-benzothiazol-2-ylmethanesulfonylmethyl,benzothiazol-4-ylmethanesulfonylmethyl,2-CF₃-benzothiazol-4-ylmethanesulfonylmethyl,benzothiazol-7-ylmethanesulfonylmethyl,2-CF₃-benzothiazol-7-ylmethanesulfonylmethyl,[1,2]benzothiazol-3-ylmethanesulfonylmethyl,[1,2]benzothiazol-4-ylmethanesulfonylmethyl,5-CF₃-[1,2]benzothiazol-4-ylmethanesulfonylmethyl,3-CF₃-[1,2]benzothiazol-4-ylmethanesulfonylmethyl,6-CF₃-[1,2]benzothiazol-7-ylmethanesulfonylmethyl,6-CN-[1,2]benzothiazol-7-ylmethanesulfonylmethyl,3-CF₃-[1,2]benzothiazol-7-ylmethanesulfonylmethyl,5-F-[1,2]benzothiazol-3-ylmethanesulfonylmethyl,[2,3]benzothiazol-7-ylmethanesulfonylmethyl,6-CF₃-[2,3]benzothiazol-7-ylmethane-sulfonylmethyl,1-CF₃-[2,3]benzothiazol-7-ylmethanesulfonylmethyl,5-CF₃-[2,3]benzothiazol-4-ylmethanesulfonylmethyl,5-CN-[2,3]benzothiazol-4-ylmethanesulfonylmethyl,1-CF₃-[2,3]benzothiazol-4-ylmethanesulfonylmethyl,4-CF₃-2-CH₃-thiazol-5-ylmethanesulfonyl-methyl,4-CF₃-thiazol-5-ylmethanesulfonylmethyl,4-CF₃-2-phenyl-thiazol-5-ylmethanesulfonylmethyl,5-CF₃-2-CH₃-thiazol-4-ylmethanesulfonylmethyl,5-CF₃-thiazol-4-ylmethanesulfonylmethyl,5-CF₃-2-phenyl-thiazol-4-ylmethanesulfonylmethyl,5-CH₃-thiazol-2-ylmethanesulfonylmethyl,5-CF₃-thiazol-2-ylmethanesulfonylmethyl,5-phenyl-thiazol-2-ylmethanesulfonylmethyl,4-CH₃-thiazol-2-ylmethanesulfonylmethyl,4-CF₃-thiazol-2-ylmethanesulfonylmethyl,4-phenyl-thiazol-2-ylmethanesulfonylmethyl,5-CH₃-2-(pyridin-2-yl)-[1,2,3]triazol-4-ylmethanesulfonylmethyl,5-CF₃-2-(pyridin-2-yl)-[1,2,3]triazol-4-ylmethanesulfonylmethyl,5-CF₃-2-(4-methylsulfonylphenyl)-[1,2,3]triazol-4-ylmethane-sulfonylmethyl,4,5-dimethyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,5-CF₃-4-CH₃-[1,2,4]triazol-3-ylmethanesulfonylmethyl,4-CH₃-5-phenyl-[1,2,4]triazol-3-ylmethane-sulfonylmethyl,5-CF₃-4-cyclopropyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,2,5-dimethyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,5-CF₃-2-CH₃-[1,2,4]triazol-3-ylmethane-sulfonylmethyl,2-CH₃-5-phenyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,2-cyclopropyl-5-phenyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,5-CF₃-1-CH₃-[1,2,4]triazol-3-ylmethane-sulfonylmethyl,1-CH₃-5-phenyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,5-CH₃-1-phenyl-[1,2,4]triazol-3-ylmethanesulfonylmethyl,3-CH₃-[1,2,4]oxadiazol-5-ylmethanesulfonylmethyl3-CF₃-[1,2,4]oxadiazol-5-ylmethanesulfonylmethyl,3-phenyl-[1,2,4]oxadiazol-5-ylmethanesulfonylmethyl,5-CH₃-[1,2,4]oxadiazol-3-ylmethanesulfonylmethyl,5-CF₃-[1,2,4]oxadiazol-3-ylmethanesulfonylmethyl,5-phenyl-[1,2,4]oxadiazol-3-ylmethanesulfonylmethyl,2-CH₃-[1,3,4]oxadiazol-5-ylmethanesulfonylmethyl,2-CF₃-[1,3,4]oxadiazol-5-ylmethanesulfonylmethyl,2-phenyl-[1,3,4]oxadiazol-5-ylmethanesulfonylmethyl,3-CH₃-[1,2,4]thiadiazol-5-ylinethanesulfonylmethyl,3-CF₃-[1,2,4]thiadiazol-5-ylmethanesulfonylmethyl,3-phenyl-[1,2,4]thiadiazol-5-ylmethanesulfonylmethyl,5-CH₃-[1,2,4]thiadiazol-3-ylmethane-sulfonylmethyl,5-CF₃-[1,2,4]thiadiazol-3-ylmethanesulfonylmethyl,5-phenyl-[1,2,4]thiadiazol-3-ylmethanesulfonylmethyl,2-CH₃-[1,3,4]thiadiazol-5-ylmethanesulfonylmethyl,2-CF₃-[1,3,4]thiadiazol-5-ylmethanesulfonylmethyl,2-phenyl-[1,3,4]thiadiazol-5-ylmethane-sulfonylmethyl,2,2-difluoropyrrolidinylmethanesulfonylmethyl,3,3-difluoropyrrolidinyl-methanesulfonylmethyl,3-CF₃—N—CH₃-pyrrol-2-ylmethanesulfonylmethyl,3-CN—N—CH₃-pyrrol-2-ylmethanesulfonylmethyl,4-CF₃—N—CH₃-pyrrol-2-ylmethanesulfonylmethyl,4-(1-CH₃-1-hydroxyethyl)-N—CH₃-pyrrol-2-ylmethanesulfonylmethyl,1,3-dimethylpyrrol-2-ylmethanesulfonylmethyl,4-CF₃—N—CH₃-pyrrol-3-ylmethanesulfonylmethyl,4-CN—N—CH₃-pyrrol-3-ylmethanesulfonylmethyl,4-CN—N-(3,3,3-trifluoropropyl)-pyrrol-3-ylmethanesulfonylmethyl,2-CF₃—N—CH₃-pyrrol-3-ylmethanesulfonylmethyl,2-CF₃—N-phenylpyrrol-3-ylmethane-sulfonylmethyl,4-CF₃-pyrrol-2-ylmethanesulfonylmethyl,4-(1-CH₃-1-hydroxyethyl)-pyrrol-2-ylmethanesulfonylmethyl,3-CH₃-pyrrol-2-ylmethanesulfonylmethyl,4-CF₃-pyrrol-3-ylmethane-sulfonylmethyl,2-CF₃-pyrrol-3-ylmethanesulfonylmethyl,3-CF₃-pyrrol-2-ylmethane-sulfonylmethyl,2-CF₃-pyrrol-4-ylmethanesulfonylmethyl,2-CF₃—N—CH₃-pyrrol-4-ylmethane-sulfonylmethyl,3-CF₃-fur-2-ylmethanesulfonylmethyl, 3-CN-fur-2-ylmethanesulfonylmethyl,3-CF₃-fur-4-ylmethanesulfonylmethyl, 3-CN-fur-4-ylmethanesulfonylmethyl,2-CF₃-fur-3-ylmethanesulfonylmethyl,3-CF₃-thiazol-2-ylmethanesulfonylmethyl,3-CN-thiazol-2-ylmethanesulfonylmethyl,3-CF₃-thiazol-4-ylmethanesulfonylmethyl,3-CN-thiazol-4-ylmethanesulfonylmethyl,2-CF₃-thiazol-3-ylmethanesulfonylmethyl,N—CH₃-3-CF₃-1H-pyrazol-5-ylmethanesulfonylmethyl,N—CH₃-3-(1-CH₃-1-hydroxyethyl)-1H-pyrazol-5-ylmethane-sulfonylmethyl,N—CH₃-3-phenyl-1H-pyrazol-5-ylmethanesulfonylmethyl,N—CH₃-3-CF₃-1H-pyrazol-4-ylmethanesulfonylmethyl,N—CH₃-4-CN-1H-pyrazol-3-ylmethanesulfonylmethyl,N-phenyl-4-CN-1H-pyrazol-3-ylmethanesulfonylmethyl,N-phenyl-3-CF₃-1H-pyrazol-4-ylmethanesulfonylmethyl,N-phenyl-5-CF₃-1H-pyrazol-4-ylmethanesulfonylmethyl,(N—CH₃-4-CF₃-1H-imidazol-2-ylmethane)-sulfonylmethyl,[N—CH₃-4-(1-CH₃-1-hydroxyethyl)-1H-imidazol-2-ylmethane]-sulfonylmethyl,(N—CH₃-4-phenyl-1H-imidazol-2-ylmethane)-sulfonylmethyl,N—CH₃-3-CF₃-1H-pyrazol-4-ylmethanesulfonylmethyl,(N—CH₃-2-CF₃-1H-imidazol-5-ylmethane)-sulfonylmethyl,(N—CH₃-2-phenyl-1H-imidazol-5-ylmethane)-sulfonylmethyl,(N—CH₃-5-CF₃-1H-imidazol-4-ylmethane)-sulfonylmethyl,(N-phenyl-5-CF₃-1H-imidazol-4-ylmethane)-sulfonylmethyl,4-CN-[1,2]oxazol-5-ylmethanesulfonylmethyl4-CN-3-phenyl-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CN-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CN-5-phenyl-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CN-isothiazol-5-ylmethanesulfonylmethyl,4-CN-3-phenyl-isothiazol-5-ylmethanesulfonylmethyl,4-CN-isothiazol-3-ylmethanesulfonylmethyl,4-CN-5-phenyl-isothiazol-3-ylmethane-sulfonylmethyl,4-CF₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-3-CH₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-3-phenyl-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CF₃-5-CH₃-[1,2]oxazol-3-ylmethanesulfonylmethyl4-CF₃-5-phenyl-[1,2]oxazol-3-ylmethanesulfonylmethyl.3-CF₃-[1,2]oxazol-4-ylmethane-sulfonylmethyl,5-CF₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,4-CF₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-3-CH₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-3-phenyl-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CF₃-5-CH₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CF₃-5-phenyl-[1,2]oxazol-3-ylmethanesulfonylmethyl,3-CF₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,5-CF₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,4-CH₃-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CH₃-3-phenyl-[1,2]oxazol-5-ylmethanesulfonylmethyl,4-CH₃-[1,2]oxazol-3-ylmethanesulfonylmethyl,4-CH₃-5-phenyl-[1,2]oxazol-3-ylmethanesulfonylmethyl,3-CH₃-[1,2]oxazol-4-ylmethane-sulfonylmethyl,5-CH₃-[1,2]oxazol-4-ylmethanesulfonylmethyl,4-CH₃-isothiazol-5-ylmethane-sulfonylmethyl,4-CH₃-3-phenyl-isothiazol-5-ylmethanesulfonylmethyl,4-CH₃-isothiazol-3-ylmethanesulfonylmethyl,4-CH₃-5-phenyl-isothiazol-3-ylmethanesulfonylmethyl,3-CH₃-isothiazol-4-ylmethanesulfonylmethyl,5-CH₃-isothiazol-4-ylmethanesulfonylmethyl,4-CF₃-2-CH₃-[1,3]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-[1,3]oxazol-5-ylmethanesulfonylmethyl,4-CF₃-2-phenyl-[1,3]oxazol-5-ylmethanesulfonylmethyl,5-CF₃-2-CH₃-[1,3]oxazol-4-yl-methanesulfonylmethyl,5-CF₃-[1,3]oxazol-4-ylmethanesulfonylmethyl,5-CF₃-2-phenyl-[1,3]oxazol-4-ylmethanesulfonylmethyl,5-CH₃-[1,3]oxazol-2-ylmethanesulfonylmethyl,5-CF₃-[1,3]oxazol-2-ylmethanesulfonylmethyl,5-phenyl-[1,3]oxazol-2-ylmethane-sulfonylmethyl,4-CH₃-[1,3]oxazol-2-ylmethanesulfonylmethyl,4-CF₃-[1,3]oxazol-2-ylmethanesulfonylmethyl,4-phenyl-[1,3]oxazol-2-ylmethanesulfonylmethyl,N-methyl-indol-2-ylmethanesulfonylmethyl,3-CF₃-indol-2-ylmethanesulfonylmethyl,3-CF₃-N-methyl-indol-2-ylmethanesulfonylmethyl,5-fluoro-N-methyl-indol-2-ylmethanesulfonylmethyl,N-methyl-indol-3-ylmethanesulfonylmethyl,2-CF₃-indol-3-ylmethanesulfonylmethyl,2-CF₃-N-methyl-indol-3-ylmethanesulfonylmethyl,5-fluoro-N-methyl-indol-3-ylmethanesulfonylmethyl,5-CF₃-N-methyl-indol-4-ylmethanesulfonylmethyl,5-CN-N-methyl-indol-4-ylmethanesulfonylmethyl,2-CF₃-N-methyl-indol-4-ylmethanesulfonylmethyl,3-CF₃-N-methyl-indol-4-ylmethanesulfonylmethyl,6-CF₃-N-methyl-indol-7-ylmethanesulfonylmethyl,6-CN—N-methyl-indol-7-ylmethanesulfonylmethyl,2-CF₃—N-methyl-indol-7-ylmethanesulfonylmethyl,3-CF₃—N-methyl-indol-7-ylmethanesulfonylmethyl,benzofuran-2-ylmethanesulfonylmethyl,3-CF₃-benzofuran-2-ylmethanesulfonylmethyl,3-CN-benzofuran-2-ylmethanesulfonylmethyl,5-F-benzofuran-2-ylmethanesulfonylmethyl,benzofuran-3-ylmethanesulfonylmethyl,2-CF₃-benzofuran-3-ylmethanesulfonylmethyl,2-CH₃-benzofuran-3-ylmethanesulfonylmethyl,5-F-benzofuran-3-ylmethanesulfonylmethyl,5-CF₃-benzofuran-4-ylmethanesulfonylmethyl,5-CN-benzofuran-4-ylmethanesulfonylmethyl,2-CF₃-benzofuran-4-ylmethanesulfonylmethyl,3-CF₃-benzofuran-4-ylmethanesulfonylmethyl,6-CF₃-benzofuran-7-ylmethanesulfonylmethyl,6-CN-benzofuran-7-ylmethanesulfonylmethyl,2-CF₃-benzofuran-7-ylmethanesulfonylmethyl,3-CF₃-benzofuran-7-ylmethanesulfonylmethyl,benzothien-2-ylmethanesulfonylmethyl,(3-CF₃-benzothien-2-ylmethane)-sulfonylmethyl,(3-CN-benzothien-2-ylmethane)-sulfonylmethyl,(5-F-benzothien-2-ylmethane)-sulfonylmethyl,benzothien-3-ylmethanesulfonylmethyl,(2-CF₃-benzothien-3-ylmethane)-sulfonylmethyl,(2-CH₃-benzothien-3-ylmethane)-sulfonylmethyl,(5-fluoro-benzothien-3-ylmethane)-sulfonylmethyl,(5-CF₃-benzothien-4-ylmethane)-sulfonylmethyl,(5-CN-benzothien-4-ylmethane)-sulfonylmethyl,(2-CF₃-benzothien-4-ylmethane)-sulfonylmethyl,(3-CF₃-benzothien-4-ylmethane)-sulfonylmethyl,(6-CF₃-benzothien-7-ylmethane)-sulfonylmethyl,(6-CN-benzothien-7-ylmethane)-sulfonylmethyl,(2-CF₃-benzothien-7-ylmethane)-sulfonylmethyl,(3-CF₃-benzothien-7-ylmethane)-sulfonylmethyl,N-methyl-benzimidazol-2-ylmethanesulfonylmethyl,(5-fluoro-N-methyl-benzimidazol-2-ylmethane)-sulfonylmethyl,(N-methyl-indazol-3-ylmethane)-sulfonylmethyl,(5-fluoro-N-methyl-indazol-3-ylmethane)-sulfonylmethyl,(2-CF₃—N-methyl-benzimidazol-4-ylmethane)-sulfonylmethyl,(2-CF₃—N-methyl-benzimidazol-7-ylmethane)-sulfonylmethyl,(N-methyl-indazol-4-ylmethane)-sulfonylmethyl,(5-CF₃—N-methyl-indazol-4-ylmethane)-sulfonylmethyl,(3-CF₃—N-methyl-indazol-4-ylmethane)-sulfonylmethyl,(6-CF₃—N-methyl-indazol-7-ylmethane)-sulfonylmethyl,(6-CN—N-methyl-indazol-7-ylmethane)-sulfonylmethyl, or(3-CF₃-N-methyl-indazol-7-ylmethane)-sulfonylmethyl.

Within the groups above, the stereochemistry at the carbon to which R⁵is attached is (R) and to which R⁴ and R⁶ are attached is (S).

Within the groups above, the stereochemistry at the carbon to which R⁵and R⁶ are attached is (R) and to which R⁴ is attached is (S).

(B) Another preferred group of compounds of Formula (I) is that wherein:

R³ is alkyl, preferably methyl or ethyl and R⁴ is alkyl, preferablymethyl, ethyl, propyl or butyl, more preferably R⁴ is methyl.Preferably, R³ and R⁴ are methyl.

(C) Yet another preferred group of compounds of Formula (I) is thatwherein R³ and R⁴ together with the carbon atom to which they areattached form cycloalkylene, preferably cyclopropylene, cyclopentylene,or cyclohexylene, more preferably cyclopropylene.

(D) Yet another preferred group of compounds of Formula (I) is thatwherein R³ and R⁴ together with the carbon atom to which they areattached form piperidin-4-yl substituted at the nitrogen atom withethyl, 2,2,2-trifluoroethyl or cyclopropyl, tetrahydropyran-4-yl,tetrahydrothiopyran-4-yl, or 1,1-dioxotetrahydrothiopyran-4-yl.

(E) Yet another preferred group of compounds of Formula (I) is thatwherein R⁶ is haloalkyl, preferably, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl and R⁷ and R⁸ arehydrogen.

(F) Yet another preferred group of compounds of Formula (I) is thatwherein R⁶ is haloalkyl, preferably, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R⁷ is haloalkyl,preferably, trifluoromethyl, 2,2,2-trifluoroethyl, or1,1,2,2,2-pentafluoroethyl, and R⁸ are hydrogen.

(G) Yet another preferred group of compounds of Formula (I) is thatwherein R⁶ is haloalkyl, preferably, difluoromethyl, trifluoromethyl,2,2,2-trifluoroethyl, or 1,1,2,2,2-pentafluoroethyl, R⁷ is alkyl,preferably, methyl, ethyl, or propyl, and R⁸ are hydrogen.

(H) Yet another preferred group of compounds of Formula (I) is thatwherein R⁶ is haloalkyl, preferably, 1,1,2,2,2-pentafluoroethyl or1,1,2,2,3,3,3-heptafluoropropyl, R⁷ and R⁸ are hydrogen.

With the preferred groups (B)-(H), more preferred groups of compoundsare those wherein R¹, R², R⁵, R⁶, R⁷ and R⁸ are as defined for group (A)above.

With the preferred groups (D)-(H), more preferred groups of compoundsare those wherein R¹, R², R³, R⁴, and R⁵ are as defined for group (A)above.

It should be noted that reference to the preferred embodiments set forthabove includes all combinations of particular and preferred groupsunless stated otherwise.

Representative compound of the compound of Formula (I) where R¹ ishydrogen, R⁶ is trifluoromethyl and other groups are as defined in TableI below are:

Cpd. Stereochem. at # *C,**C,***C R² R³ R⁴ R³ + R⁴ R⁵ R⁷ R⁸ 1 (S,R,S)cyclopropyl H n-propyl cyclopropylmethanesulfonylmethyl H 4-Fphenyl 2(S,R,S) cyclopropyl H n-propyl pyridin-3-ylmethanesulfonyl-methyl H4-Fphenyl 3 (R,R,S) cyclopropyl H n-propylcyclopropylmethanesulfonylmethyl H 4-Fphenyl 4 (*S,**R) cyclopropylcyclopropylene cyclopropylmethanesulfonylmethyl H 4-Fphenyl 5 (*S,**R)cyclopropyl CH₃ CH₃ cyclopropylmethanesulfonylmethyl H 4-Fphenyl 6(**R,***S) cyclopropyl H ethyl cyclopropylmethanesulfonylmethyl H H 7(*S,**R) cyclopropyl cyclopropylene pyridin-3-ylmethanesulfonyl-methyl H4-Fphenyl 8 (R,R,S) cyclopropyl H ethyl 4-CF₃pyridin-3-ylmethane- H4-Fphenyl sulfonylmethyl 9 (S,R,S) cyclohexyl H ethylcyclopropylmethanesulfonylmethyl H 4-Fphenyl 10 (S,R,S) benzyl H ethylcyclopropylmethanesulfonylmethyl H 4-Fphenyl 11 (*S,**R) benzyl CH₃ CH₃pyridin-3-ylmethanesulfonylmethyl H 4-Fphenyl 12 (*S,**R) cyclopropylCH₃ CH₃ pyridin-3-ylmethanesulfonylmethyl H 4-Fphenyl 13 (*S,**R) benzylCH₃ CH₃ cyclopropylmethanesulfonylmethyl H 4-Fphenyl 14 (*R,**R) benzylCH₃ CH₃ cyclopropylmethanesulfonylmethyl H 4-Fphenyl 15 (*S,**R) benzylCH₃ CH₃ cyclopropylmethanesulfonylmethyl H 4-Fphenyl 16 (R,R,S)cyclopropyl H ethyl pyridin-3-ylmethanesulfonylmethyl H 4-Fphenyl 17(S,R,S) cyclopropyl H ethyl pyridin-2-ylmethanesulfonylmethyl H 3,4-diFphenyl 18 (*S,**R) cyclopropyl CH₃ CH₃ 4-CF₃pyridin-3-ylmethane- H4-Fphenyl sulfonylmethyl 19 (S,R,S) cyclopropyl H ethyl2-pyridin-2-ylethanesulfonylmethyl H 4-Fphenyl 20 (*S,**R) cyclopropylCH₃ CH₃ 2-pyridin-2-ylethanesulfonylmethyl H 4-Fphenyl 21 (*S,**R)cyclopropyl cyclopropyl 2-pyridin-2-ylethanesulfonylmethyl H 4-Fphenyl22 (*S,**R) cyclopropyl cyclopropyl 4-CF₃pyridin-3-ylmethane- H4-Fphenyl sulfonylmethyl 23 (*S,**R) cyclopropyl CH₃ CH₃pyridin-3-ylmethanesulfonylmethyl H 2,4- diFphenyl 24 (*R,**R)cyclopropyl CH₃ CH₃ pyridin-3-ylmethanesulfonylmethyl H 2,4- diFphenyl25 (*S,**R) cyclopropyl cyclopropyl pyridin-3-ylmethanesulfonylmethyl H2,4- diFphenyl 26 (*R,**R) cyclopropyl cyclopropylpyridin-3-ylmethanesulfonylmethyl H 2,4- diFphenyl 27 (*S,**R)cyclopropyl cyclopropyl 1-oxopyridin-3-ylmethane- H 2,4- sulfonylmethyldiFphenyl 28 (*R,**R) cyclopropyl cyclopropyl 1-oxopyridin-3-ylmethane-H 2,4- sulfonylmethyl diFphenyl 29 (*S,**R) cyclopropyl CH₃ CH₃4-CNpyridin-3-ylmethane- H 4-Fphenyl sulfonylmethyl 30 (S,R,S)cyclopropyl H ethyl 2-(2,3-dioxoindol-1-yl)- H 4-Fphenylethanesulfonylmethyl 31 (*S,**R) cyclopropyl cyclohexyl pyridin-3-ylmethanesulfonylmethyl H 4-Fphenyl 32 (**R,***S) cyclopropyl CH₃ CH₃2-cyanophenylmethanesulfonylmethyl H H 33 (*S,**R) cyclopropyl CH₃ CH₃2-CH₃SO₂phenylmethane- H 4-F-phenyl sulfonylmethyl 34 (*S,**R)cyclopropyl CH₃ CH₃ 2-(2-oxoimidazolidin-l-yl)- H 4-F-phenylethylsulfonylmethyl 35 (S,R,S) cyclopropyl H ethyl phenylsulfonylmethylH 4-F-phenyl 36 (*S,**R) cyclopropyl CH₃ CH₃3-CH₃SO₂phenylmethanesulfonylmethyl H 4-F-phenyl 37 (S,R,S) cyclopropylH ethyl 2-cyclopropylmethanesulfonylethyl H 4-F-phenyl 38 (*S,**R)cyclopropyl CH₃ CH₃ 4-CH₃SO₂phenylmethanesulfonylmethyl H 4-F-phenyl 39(S,R,S) cyclopropyl H cyclobutylmethyl cyclopropylmethanesulfonylmethylH 4-F-phenyl 40 (*S,**R) cyclopropyl cyclopropylene2-cyanophenylmethanesulfonylmethyl H 4-Fphenyl 41 (*S,**R) cyclopropylCH₃ CH₃ 2-cyanophenylmethanesulfonylmethyl H 4-Fphenyl 42 (*S,**R,***S)cyclopropyl H ethyl 4-(4-fluorobenzoyl)- H 4-Fphenylpiperazin-l-ylsulfonylmethyl 43 (*S,**R) cyclopropyl CH₃ CH₃4-(4-fluorobenzoyl)- H 4-Fphenyl piperazin-1-ylsulfonylmethyl 44(*S,**S,***S) cyclopropyl H ethyl 2-chlorobenzyl H 4-Fphenyl 45(*S,**R,***S) cyclopropyl H ethyl biphenyl-4-ylsulfonylmethyl H4-Fphenyl 46 (*S,**R,***S) cyclopropyl H ethyl3-trifluoromethylsulfonylmethyl H 4-Fphenyl 47 (*S,**R,***S) cyclopropylH ethyl 3-methylsulfonylbenzylsulfonylmethyl H 4-Fphenyl 48(*S,**R,***S) cyclopropyl H ethyl cyclopropylmethanesulfonylmethyl H4-Fphenyl 49 (*S,**R,***S) cyclopropyl H ethyl4-trifluorophenylsulfonylmethyl H 4-Fphenyl 50 (*S,**R,***S) cyclopropylH ethyl 4-methylsulfonylphenylsulfonylmethyl H 4-Fphenyl 51(*S,**S,***S) cyclopropyl H ethyl 2-cyclohexylethyl H 4-Fphenyl 52(*S,**R,***S) cyclopropyl H ethyl pyrid-3-ylmethylsulfonylmethyl H4-Fphenyl 53 (**S,***S) cyclopropyl H ethyl benzyloxymethyl H 4-Fphenyl54 (*S,**R,***S) cyclopropyl H ethyl naphth-2-ylsulfonylmethyl H4-Fphenyl 55 (*S,**S,***S) cyclopropyl H ethyl 2-phenylsulfonylethyl H4-Fphenyl 56 (*S,**S,***S) cyclopropyl H ethyl tert-butylmethyl H4-Fphenyl 57 (*S,**R,***S) cyclopropyl H ethyl pyrid-3-ylsulfonylmethylH 4-Fphenyl 58 (*S,**R,***S) cyclopropyl H ethylmorpholin-4-ylsulfonylmethyl H 4-Fphenyl 59 (*S,**R,***S) cyclopropyl Hethyl phenylylsulfonylmethyl H phenyl 60 (*S,**R,***S) cyclopropyl Hethyl naphth-1-ylsulfonylmethyl H 4-Fphenyl 61 (*S,**S,***S) cyclopropylH ethyl 3,3-dimethylpentyl H 4-Fphenyl 62 (**R,***S) cyclopropyl H ethylcyclopropylmethylsulfonylmethyl H tetrahydro- pyran-4-yl 63(*S,**R,***S) cyclopropyl H ethyl3,5-trifluoromethylphenylsulfonylmethyl H 4-Fphenyl 64 (*S,**R,***S)cyclopropyl H ethyl quinolin-3-ylsulfonylmethyl H 4-Fphenyl 65(*S,**R,***S) cyclopropyl H ethyl pyrid-4-ylsulfonylmethyl H 4-Fphenyl66 (*S,**S,***S) cyclopropyl H ethyl 2,2-difluoro-3-phenylpropyl H4-Fphenyl 67 (*S,**S,***S) cyclopropyl H ethyl 2,2,2-trifluoroethyl H4-Fphenyl 68 (*S,**R,***S) cyclopropyl H ethyl3-methoxyphenylsulfonylmethyl H 4-Fphenyl 69 (*S,**R,***S) cyclopropyl Hethyl 4-methoxyphenylsulfonylmethyl H 4-Fphenyl 70 (*S,**R,***S)cyclopropyl H ethyl 2-methoxyphenylsulfonylmethyl H 4-Fphenyl 71(*S,**R,***S) cyclopropyl H ethyl isoquinolin-4-ylsulfonylmethyl H4-Fphenyl 72 (*S,**R,***R) cyclopropyl H ethyl phenylsulfonylmethyl H4-Fphenyl 73 (*S,**S,***S) cyclopropyl H ethyl isobutyl H 4-Fphenyl 74(*S,**R,***R) pyrazol-3-yl H ethyl cyclopropylmethylsulfonylmethyl H4-Fphenyl 75 (*S,**S,***R) cyclopropyl H ethyl benzyl H 4-Fphenyl 76(*S,**R,***R) cyclopropyl H ethyl cyclopropylmethylsulfonylmethyl Htetrahydro- pyran-4-yl 77 (*S,**R,***R) cyclopropyl H ethylphenylsulfonylmethyl H tetrahydro- pyran-4-yl 78 (*S,**S,***S)cyclopropyl H ethyl 2-methanesulfonylethyl H 4-Fphenyl 79 (*S,**S,***S)cyclopropyl H ethyl cyclopropylmethyl H 4-Fphenyl 80 (*S,**S,***S)cyclopropyl H ethyl cyclopropylmethyl H tetrahydro- pyran-4-yl 81(*S,**S,***S) cyclopropyl H ethyl 2,2-difluoro-4-methylpentyl H4-Fphenyl 82 (*S,**S,***S) cyclopropyl H ethyl phenylsulfonylaminomethylH 4-Fphenyl 83 (*S,**S,***S) cyclopropyl H ethylisopropylsulfonylarninomethyl H 4-Fphenyl 84 (*S,**S,***S) cyclopropyl Hethyl methylsulfonylaminomethyl H 4-Fphenyl 85 (*S,**S,***S) cyclopropylH ethyl 2-(4-trifluoromethyl- H 4-Fphenyl phenylsulfonyl)ethyl 86(*S,**S,***S) cyclopropyl H ethyl2-(4-trifluoromethylphenylsulfanyl)ethyl H 4-Fphenyl 87 (*S,**S,***S)cyclopropyl H ethyl 2-methylsulfinylethyl H 4-Fphenyl 88 (*S,**S,***S)cyclopropyl H ethyl 2-pyrid-3-ylsulfonylethyl H 4-Fphenyl 89(*S,**S,***S) cyclopropyl H ethyl 3-phenylpropyl H 4-Fphenyl 90(*S,**S,***S) cyclopropyl H ethyl2-(4-methylsulfonylphenylsulfonyl)ethyl H 4-Fphenyl 91 (*S,**S,***S)cyclopropyl H ethyl 1-(tert-butoxycarbonyl)- H 4-Fphenylpiperidin-4-ylmethyl 92 (*S,**S,***S) cyclopropyl H ethyl 2-chlorobenzylH 4-Fphenyl 93 (*S,**S,***S) cyclopropyl H ethyl2,2-difluoro-2-phenylethyl H tetrahydro- pyran-4-yl 94 (*S,**S,***S)cyclopropyl H ethyl 1-methylsulfonylpiperidin-4-ylmethyl H 4-Fphenyl 95(*S,**S,***S) cyclopropyl H ethyl 1-aminocarbonylpiperidin-4-ylmethyl H4-Fphenyl 96 (*S,**S,***S) cyclopropyl H ethyl 1-methylcyclopentylmethylH 4-Fphenyl 97 (*S,**S,***S) pyrazol-3-yl H ethyl1-methylcyclopentylmethyl H 4-Fphenyl 98 (*S,**S,***S) cyclopropyl Hethyl 1-methylcyclopentylmethyl H tetrahydro- pyran-4-yl

Representative compound of the compound of Formula (I) where R¹, R⁷ andR⁸ are hydrogen and other groups are as defined in Table II below are:

Stereochem. Cpd. At # **C***C R² R³ R⁴ R³ + R⁴ R⁵ R⁶ 1 (**R,***S)cyclopropyl H ethyl pyridine-3-ylmethanesulfonylmethyl1,1,2,2,2-pentafluoroethyl 2 (**R,***S) cyclopropyl H ethylcyclopropylmethanesulfonyl-methyl 1,1,2,2,2-pentafluoroethyl 3(**R,***S) cyclopropyl H ethyl pyridine-3-ylmethanesulfonyl-methyltrifluoromethyl 4 (**R,***S) cyclopropyl H n-propylcyclopropylmethanesulfonyl-methyl 1,1,2,2,2-pentafluoroethyl 5(**R,***S) cyclopropyl H n-propyl pyridine-3-ylmethanesulfonylmethyl1,1,2,2,2-pentafluoroethyl 6 (**R,***S) cyclopropyl H ethylcyclopropylmethanesulfonyl-methyl 1,1,2,2,-tetrafluoroethyl 7 (**R,***S)cyclopropyl H ethyl pyridine-3-ylmethanesulfonyl-methyl1,1,2,2,-tetrafluoroethyl 8 (**R,***S) cyclopropyl H ethylcyclopropylmethanesulfonylmethyl 1,1,2,2,3,3,3- heptafluoropropyl 7(**R,***S) cyclopropyl H ethyl pyridine-3-ylmethanesulfonyl-methyl1,1,2,2,3,3,3- heptafluoropropyl 8 (**R,***S) cyclopropyl H ethyl4-CF₃pyridin-3 -ylmethane-sulfonylmethyl 1,1,2,2,2-pentafluoroethyl 9(**R,***S) cyclopropyl H ethyl 2-(cyclopropylmethanesulfonyl)-ethyl1,1,2,2,2-pentafluoroethyl 10 (**R,***S) cyclopropyl H ethyl2-(pyridine-3-ylmethanesulfonyl)-ethyl 1,1,2,2,2-pentafluoroethyl 11(**R,***S) cyclopropyl H ethyl 2-(cyclopropylmethanesulfonyl)-ethyltrifluoromethyl 12 (**R,***S) cyclopropyl H ethylcyclopropylmethanesulfonylmethyl chlorodifluoromethyl 13 (**R,***S)cyclopropyl H ethyl cyclopropylmethanesulfonylmethyl —(CF₂)₃CHF₂ 14(**R,***S) cyclopropyl H ethyl pyridine-3-ylmethanesulfonylmethyl—(CF₂)₃CHF₂ 15 (**R,***S) cyclopropyl H ethylpiperidin-1-ylsulfonylmethyl trifluoromethyl 16 (**R,***S) cyclopropyl Hethyl cyclopropylmethanesulfonylmethyl perfluoropentyl 17 (**R)cyclopropyl H ethyl cyclopropylmethanesulfonylmethyl1,1,2,2,3,3-hexafluoropropyl 18 (**R,***S) cyclopropyl CH₃ CH₃2-methylsulfonylbenzylsulfonylmethyl trifluoromethyl 19 (**R,***S)cyclopropyl CH₃ CH₃ 3-methylsulfonylbenzylsulfonylmethyl trifluoromethyl20 (**R,***S) cyclopropyl H cyclobutyl- cyclopropylmethanesulfonylmethylperfluoropropyl methyl 21 (**R,***S) cyclopropyl H ethylpyrid-2-ylmethanesulfonylmethyl 1,1,2,2,3,3,4,4- octafluorobutyl 22(**R,***S) cyclopropyl H ethyl pyrid-2-ylmethanesulfonylmethyl 1,1,2,2,3,3-hexafluorobutyl 23 (**R,***S) cyclopropyl H ethylpyrid-3-ylmethanesulfonylmethyl 1,1,2,2,3,3-hexafluorobutylThe following represent compounds of the invention.

Cpd. Stereochem. at # *C,**C,***C R² R³ R⁴ R³ + R⁴ R⁵ R⁷ R⁸ 1 (*S,**R)cyclopropyl cyclopropylene 4-CF₃-pyridin-3-ylmethane-sulfonylmethyl H4-Fphenyl 2 (*S,**R) cyclopropyl CH₃ CH₃4-CF₃-pyridin-3-ylmethane-sulfonylmethyl H 4-Fphenyl 3 (*S,**R)cyclopropyl CH₃ CH₃ 4-CF₃-pyridin-3-ylmethane-sulfonylmethyl H2,4-diFphenyl 4 (*S,**R) cyclopropyl CH₃ CH₃pyridin-3-ylmethanesulfonylmethyl H 2,4-diFphenyl 5 (*S,**R) cyclopropylcyclopropylene 4-CF₃-pyridin-3-ylmethane-sulfonylmethyl H 2,4-diFphenyl6 (*S,**R) cyclopropyl cyclopropylene pyridin-3-yhnethanesulfonylmethylH 2,4-diFphenyl

General Synthetic Scheme

Compounds of this invention can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis,Mo.) or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition) and Larock's ComprehensiveOrganic Transformations (VCH Publishers Inc., 1989). These schemes aremerely illustrative of some methods by which the compounds of thisinvention can be synthesized, and various modifications to these schemescan be made and will be suggested to one skilled in the art havingreferred to this disclosure.

The starting materials and the intermediates of the reaction may beisolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., more preferably from about 0° C. to about 125° C.and most preferably at about room (or ambient) temperature, e.g., about20° C.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1999.

Compounds of Formula (I) where R¹, R², R³, R⁴, R⁵, R⁶ and R⁸ are asdefined in the Summary of the Invention and R⁷ is hydrogen can beprepared by proceeding as in the following Reaction Scheme 1 below.

Reaction of a ketone of formula 1 where R⁶ and R⁸ are as defined in theSummary of the Invention with an α-amino ester of formula 2 where R is acarboxy protecting group, preferably an alkyl group, preferably methyl,and R⁵ is as defined in the Summary of the Invention under reductiveamination reaction conditions provide a compound of formula 3. Thereaction is carried out in the presence of a suitable dehydrating agentsuch as TiCl₄, magnesium sulfate, isopropyl trifluoroacetate, in thepresence of a base such as diisopropylethylamine, pyridine, and the likeand in a suitable organic solvent such as methylene chloride to give animine. The imine is reduced with a suitable reducing agent such assodium borohydride, sodium cyanoborohydride, and the like in a suitableorganic solvent such as methanol, ethanol, and the like.

Compounds of formula 1 such as 2,2,2-trifluoromethylacetophenone and2,2,2,4′-tetrafluoroacetophenone are commercially available. Others canbe prepared by methods well known in the art. α-Amino esters of formula2 can be prepared by methods well known in the art e.g., PCTApplications Publication Nos. WO 03075836, WO 00/55144, WO 01/19816, WO02/20485, WO 03/029200, U.S. Provisional Application No. 60/422,337,U.S. Pat. Nos. 6,353,017B1, 6,492,662B1, 6,353,017 B1 and 6,525,036B1,6,229,011B1, 6,610,700, the disclosures of which are incorporated hereinby reference in their entirety.

Hydrolysis of the ester group in compound 3 provides a compound offormula 4. The hydrolysis conditions depend on the nature of theprotecting group. For example, when R is alkyl the hydrolysis is carriedout under aqueous basic hydrolysis reaction conditions to give thecorresponding acid of formula 4. The reaction is typically carried outwith cesium carbonate, lithium hydroxide, and the like in an aqueousalcohol such as methanol, ethanol, and the like.

Compound 4 is then reacted with an α-hydroxyketoamide of formula 5 togive a compound of Formula 6. The reaction is typically carried out inthe presence of a suitable coupling agent e.g.,benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate(PyBOP®), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uroniumhexafluorophosphate (HBTU),O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uroniumhexafluorophosphate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or1,3-dicyclohexylcarbodiimide (DCC), optionally in the presence of1-hydroxy-benzotriazole (HOBT), and a base such asN,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and thelike. The reaction is typically carried out at 20 to 30° C., preferablyat about 25° C., and requires 2 to 24 h to complete. Suitable reactionsolvents are inert organic solvents such as halogenated organic solvents(e.g., methylene chloride, chloroform, and the like), acetonitrile,N,N-dimethylformamide, ethereal solvents such as tetrahydrofuran,dioxane, and the like.

Alternatively, the above coupling step can be carried out by firstconverting 4 into an active acid derivative such as succinimide esterand then reacting it with an α-hydroxyketoamide of formula 5. Thereaction typically requires 2 to 3 h to complete. The conditionsutilized in this reaction depend on the nature of the active acidderivative. For example, if it is an acid chloride derivative of 4, thereaction is carried out in the presence of a suitable base (e.g.triethylamine, diisopropylethylamine, pyridine, and the like). Suitablereaction solvents are polar organic solvents such as acetonitrile,N,N-dimethylformamide, dichloromethane, or any suitable mixturesthereof. Compounds of formula 5 can be prepared by methods well known inthe art e.g., they can be prepared by the procedures described in PCTapplication publication No. WO 02/18369, the disclosure of which isincorporated herein by reference in its entirety.

Oxidation of the hydroxyl group in compound 6 with a suitable oxidizingagent such as OXONE® provides a compound of Formula (I).

Alternatively, compounds of Formula (I) where R¹, R², R³, R⁴, R⁵, R⁶ andR⁸ are as defined in the Summary of the Invention and R⁷ is hydrogen canbe prepared by proceeding as in the following Reaction Scheme 2 below.

Reaction of a compound of formula 8 where R⁵ is as defined in theSummary of the Invention and PG is a suitable oxygen protecting groupwith a hemiacetal of formula 7 where R⁶ is as defined in the Summary ofthe Invention provides an imine compound of of formula 9. Treatment of 9with an organolithium compound of formula R⁸Li where R⁸ is not hydrogenprovides compound 10. Removal of the oxygen protecting group, followedby oxidation of the resulting alcohol 11 provides a compound of formula4 which is then converted to a compound of Formula (I) as described inScheme 1 above. Suitable oxygen protecting groups and reactionconditions for putting them on and removing them can be found in Greene,T. W.; and Wuts, P. G. M.; Protecting Groups in Organic Synthesis; JohnWiley & Sons, Inc. 1999.

Alternatively, compounds of Formula (I) where R¹, R², R³, R⁴, R⁵, R⁶ andR⁸ are as defined in the Summary of the Invention and R⁷ is hydrogen canbe prepared by proceeding as in the following Reaction Scheme 3 below.

Reaction of an amino acid compound of formula 2 where R is alkyl and R⁵is as defined in the Summary of the Invention with a hemiacetal compoundof formula 7 provides a 2-(1-hydroxy-2,2,2-trifluoroethylamino)acetatecompound of formula 12. The reaction is carried out in the presence of acatalytic amount of an acid such as p-toluenesulfonic acid and in anaromatic hydrocarbon solvent such as toluene, benzene, and the like.

Treatment of 12 with a compound of formula R⁸H where R⁸ is aryl orheteroaryl under Friedel-Crafts reaction conditions or trialkylaluminumin toluene provides a compound of formula 3 which is then converted to acompound of Formula (I) as described above.

Alternatively, compounds of Formula (I) where R¹, R², R³, R⁴, R⁵, R⁶ andR⁸ are as defined in the Summary of the Invention and R⁷ is hydrogen canbe prepared by proceeding as in the following Reaction Scheme 4 below.

Reaction of a compound of formula 13 where R⁶ and R⁸ is as defined inSummary of the Invention with a compound of formula 14 where R′ ishydrogen or a carboxy protecting group and R^(z) is R⁵ or a precursorgroup (e.g., -alkylene-S-trityl, -alkylene-S-alkylene-heteroaryl, andthe like) to R⁵ group provides a compound of formula 15. The reaction iscarried out in a suitable organic solvent, including but not limited to,diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, xylene,and the like, or mixtures thereof and optionally in the presence of anorganic or inorganic base. Preferably, the organic base istriethylamine, pyridine, N-methylmorpholine, collidine,diisopropylethylamine, and the like. Preferably, the inorganic base iscesium carbonate, sodium carbonate, sodium bicarbonate, and the like.The reaction is optionally carried out in the presence of a drying agentsuch as molecular sieves. Preferably, the reaction is carried out atroom temperature.

Compounds of formula 13 can be prepared by methods well known in theart. For example, a compound of formula 13 where R⁸ is phenyl or4-fluorophenyl and R⁶ is trifluoromethyl can be readily prepared fromcommercially available 2,2,2-trifluoroacetophenone or2,2,2,4′-tetrafluoroacetophenone respectively, by reducing the ketogroup to an alcoholic group by suitable reducing agent such as sodiumborohydride, lithium aluminum hydride, and the like. The solvent useddepends on the type of reducing agent. For example, when sodiumborohydride is used the reaction is carried out in an alcoholic organicsolvent such as methanol, ethanol, and the like. When lithium aluminumhydride is used the reaction is carried out in an ethereal solvent suchas tetrahydrofuran, and the like. Reaction of2,2,2-trifluoro-1-phenylethanol or2,2,2-trifluoro-1-(4-fluorophenyl)ethanol with triflic anhydride ortrifluoromethanesulfonyl chloride provides the desired compound.Compounds of formula 13 where R⁷ and R⁸ are hydrogen and R⁶ is1,1,2,2,2-pentafluoroethyl can be prepared from commercially available2,2,3,3,3-pentafluoropropan-1-ol can as described above. Opticallyenriched compound of formula 15 can be obtained by reduction of thecorresponding halogenated acetophenone with a suitable reducing agentsuch as catecholborane or BH₃-DMS complex in the presence of a suitablecatalyst such as (S) or (R)-methyl CBS oxazaborolidine catalyst or (S)or (R)-α,α-diphenyl-2-pyrrolidine-methanol in the presence of BBN toprovide chiral alcohol which is then converted to compound 13 asdescribed above. Compounds of formula 14 are either commerciallyavailable or they can be prepared by methods well known in the art.

Removal of the carboxy protecting group from a compound of formula 15where R′ is a protecting group provides a compound of formula 16. Theconditions used to remove the carboxy protecting group depend on thenature of the carboxy protecting group. For example, if R′ is alkyl, itis removed under basic hydrolysis reaction conditions utilizing aqueousbase such as aqueous lithium hydroxide, sodium hydroxide, and the likein an alcoholic solvent such as methanol, ethanol, and the like.Additionally, if the R^(z) group in compound 14 is a precursor group toR⁵, it can be converted to R⁵ prior or after the ester hydrolysis step.

Compound 15 (where R′ is hydrogen) or 16 is then converted to anactivated acid derivative 17 (X is a leaving group) and which uponreaction with an aminoacetonitrile compound of formula 5 provides acompound of Formula (I) when R^(z) is R⁵ or a precursor compound to (I)when R^(z) is a precursor group to R⁵. The activated acid derivative canbe prepared and then reacted with compound 5 in a stepwise manner or theactivated acid derivative can be generated in situ in the presence ofcompound 5. For example, if the activated acid is acid halide it isfirst prepared by reacting 16 with a halogenating agent such as thionylchloride, oxalyl chloride and the like and then reacted with compound 5.Alternatively, the activated acid derivative is generated in situ byreacting compound 16 and 5 in the presence of a suitable coupling agente.g., benzotriazole-1-yloxytrispyrrolidinophosphoniumhexafluorophosphate (PyBOP®),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate(HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uroniumhexafluorophosphate (HATU),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC),1,3-dicyclohexylcarbodiimide (DCC), an the like, optionally in thepresence of 1-hydroxybenzotriazole (HOBT), and in the presence of a basesuch as N,N-diisopropylethylamine, triethylamine, N-methylmorpholine,and the like. Suitable reaction solvents are inert organic solvents suchas halogenated organic solvents (e.g., methylene chloride, chloroform,and the like), acetonitrile, N,N-dimethylformamide, ethereal solventssuch as tetrahydrofuran, dioxane, and the like. If R^(z) is a precursorgroup to R⁵, it is converted to R⁵ group to provide a compound ofFormula (I) e.g, conversion of -alkylene-S-alkylene-heteroaryl to-alkylene-SO₂-alkylene-heteroaryl under oxidation reaction conditions.

A compound of Formula (I) can be converted to other compounds of Formula(I). For example:

A compound of Formula (I) containing a hydroxy group may be prepared byde-alkylationlbenzylation of an alkoxy/benzyloxy substituent; thosecontaining an acid group, by hydrolysis of an ester group; and thosecontaining a cyano, by displacement of a bromine atom on thecorresponding compounds of Formula (I). A compound of Formula (I)containing a cyano group can be converted to a corresponding carboxycontaining compound by hydrolysis of the cyano group. The carboxy group,in turn, can be converted to an ester group.

A compound of Formula (I) can be prepared as a pharmaceuticallyacceptable acid addition salt by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid.Alternatively, a pharmaceutically acceptable base addition salt of acompound of Formula (I) can be prepared by reacting the free acid formof the compound with a pharmaceutically acceptable inorganic or organicbase. Inorganic and organic acids and bases suitable for the preparationof the pharmaceutically acceptable salts of compounds of Formula (I) areset forth in the definitions section of this Application. Alternatively,the salt forms of the compounds of Formula (I) can be prepared usingsalts of the starting materials or intermediates.

The free acid or free base forms of the compounds of Formula (I) can beprepared from the corresponding base addition salt or acid addition saltform. For example, a compound of Formula (I) in an acid addition saltform can be converted to the corresponding free base by treating with asuitable base (e.g., ammonium hydroxide solution, sodium hydroxide, andthe like). A compound of Formula (I) in a base addition salt form can beconverted to the corresponding free acid by treating with a suitableacid (e.g., hydrochloric acid, etc).

The N-oxides of compounds of Formula (I) can be prepared by methodsknown to those of ordinary skill in the art. For example, N-oxides canbe prepared by treating an unoxidized form of the compound of Formula(I) with an oxidizing agent (e.g., trifluoroperacetic acid, permaleicacid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, orthe like) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0° C.Alternatively, the N-oxides of the compounds of Formula (I) can beprepared from the N-oxide of an appropriate starting material.

Compounds of Formula (I) in unoxidized form can be prepared fromN-oxides of compounds of Formula (I) by treating with a reducing agent(e.g., sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride,sodium borohydride, phosphorus trichloride, tribromide, or the like) ina suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueousdioxane, or the like) at 0 to 80° C.

Prodrug derivatives of the compounds of Formula (I) can be prepared bymethods known to those of ordinary skill in the art (e.g., for furtherdetails see Saulnier et al. (1994), Bioorganic and Medicinal ChemistryLetters, Vol. 4, p. 1985). For example, appropriate prodrugs can beprepared by reacting a non-derivatized compound of Formula (I) with asuitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like).

Protected derivatives of the compounds of Formula (I) can be made bymeans known to those of ordinary skill in the art. A detaileddescription of the techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, Protecting Groupsin Organic Synthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds of the present invention may be conveniently prepared orformed during the process of the invention, as solvates (e.g. hydrates).Hydrates of compounds of the present invention may be convenientlyprepared by recrystallisation from an aqueous/organic solvent mixture,using organic solvents such as dioxin, tetrahydrofuran or methanol.

Compounds of Formula (I) can be prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds, separating the diastereomers and recovering the opticallypure enantiomer. While resolution of enantiomers can be carried outusing covalent diasteromeric derivatives of compounds of Formula (I),dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and can bereadily separated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

Preparation of Biological Agents

In practicing this invention several processes for the generation orpurification of biological agents are used. Methods for preparing thebiologics are well known in the art as discussed below.

Monoclonal antibodies can be prepared using standard techniques wellknown in the art such as by the method of Kohler and Milstein, Nature1975, 256:495, or a modification thereof, such as described by Buck etal. 1982, In Vitro 18:377. Typically, a mouse or rat is immunized withthe MenB PS derivative conjugated to a protein carrier, boosted and thespleen (and optionally several large lymph nodes) removed anddissociated into single cells. If desired, the spleen cells may bescreened (after removal of non-specifically adherent cells) by applyinga cell suspension to a plate or well coated with the antigen. B-cells,expressing membrane-bound immunoglobulin specific for the antigen, willbind to the plate, and will not be rinsed away with the rest of thesuspension. Resulting B-cells, or all dissociated spleen cells, are theninduced to fuse with myeloma cells to form hybridomas. Representativemurine myeloma lines for use in the hybridizations include thoseavailable from the American Type Culture Collection (ATCC).

Chimeric antibodies composed of human and non-human amino acid sequencesmay be formed from the mouse monoclonal antibody molecules to reducetheir immunogenicity in humans (Winter et al. Nature 1991 349:293;Lobuglio et al. Proc. Nat. Acad. Sci. USA 1989 86:4220; Shaw et al. J.Immunol. 1987 138:4534; and Brown et al. Cancer Res. 1987 47:3577;Riechmann et al. Nature 1988 332:323; Verhoeyen et al. Science 1988239:1534; and Jones et al. Nature 1986 321:522; EP Publication No.519,596, published Dec. 23, 1992; and U.K. Patent Publication No. GB2,276,169, published Sep. 21, 1994).

Antibody molecule fragments, e.g., F(ab′)₂, FV, and sFv molecules, thatare capable of exhibiting immunological binding properties of the parentmonoclonal antibody molecule can be produced using known techniques.Inbar et al. Proc. Nat. Acad. Sci. USA 1972 69:2659; Hochman et al.Biochem. 1976 15:2706; Ehrlich et al. Biochem. 1980 19:4091; Huston etal. Proc. Nat. Acad. Sci. USA 1988 85(16):5879; and U.S. Pat. Nos.5,091,513 and 5,132,405, and U.S. Pat. No. 4,946,778.

In the alternative, a phage-display system can be used to expand themonoclonal antibody molecule populations in vitro. Saiki, et al. Nature1986 324:163; Scharf et al. Science 1986 233:1076; U.S. Pat. Nos.4,683,195 and 4,683,202; Yang et al. J. Mol. Biol. 1995 254:392; Barbas,III et al. Methods: Comp. Meth Enzymol. 1995 8:94; Barbas, III et al.Proc. Natl. Acad. Sci. USA 1991 88:7978.

The coding sequences for the heavy and light chain portions of the Fabmolecules selected from the phage display library can be isolated orsynthesized, and cloned into any suitable vector or replicon forexpression. Any suitable expression system can be used, including, forexample, bacterial, yeast, insect, amphibian and mammalian systems.Expression systems in bacteria include those described in Chang et al.Nature 1978 275:615, Goeddel et al. Nature 1979 281:544, Goeddel et al.Nucleic Acids Res. 1980 8:4057, European Application No. EP 36,776, U.S.Pat. No. 4,551,433, deBoer et al. Proc. Natl. Acad. Sci. USA 198380:21-25, and Siebenlist et al. Cell 1980 20:269.

Expression systems in yeast include those described in Hinnen et al.Proc. Natl. Acad. Sci. USA 1978 75:1929, Ito et al. J. Bacteriol. 1983153:163, Kurtz et al. Mol. Cell. Biol. 1986 6:142, Kunze et al. J BasicMicrobiol. 1985 25:141, Gleeson et al. J. Gen. Microbiol. 1986 132:3459,Roggenkamp et al. Mol. Gen. Genet. 1986 202:302, Das et al. J.Bacteriol. 1984 158:1165, De Louvencourt et al. J. Bacteriol. 1983154:737, Van den Berg et al. Bio/Technology 1990 8:135, Kunze et al. J.Basic Microbiol. 1985 25:141, Cregg et al. Mol. Cell. Biol. 1985 5:3376,U.S. Pat. Nos. 4,837,148 and 4,929,555, Beach et al. Nature 1981300:706, Davidow et al. Curr. Genet. 1985 10:380, Gaillardin et al.Curr. Genet. 1985 10:49, Ballance et al. Biochem. Biophys. Res. Commun.1983 112:284-289, Tilburn et al. Gene 1983 26:205-221, Yelton et al.Proc. Natl. Acad. Sci. USA 1984 81:1470-1474, Kelly et al. EMBO J. 19854:475479; European Application No. EP 244,234, and InternationalPublication No. WO 91/00357.

Expression of heterologous genes in insects can be accomplished asdescribed in U.S. Pat. No. 4,745,051, European Application Nos. EP127,839 and EP 155,476, Vlak et al. J. Gen. Virol. 1988 69:765-776,Miller et al. Ann. Rev. Microbiol. 1988 42:177, Carbonell et al. Gene1988 73:409, Maeda et al. Nature 1985 315:592-594, Lebacq-Verheyden etal. Mol. Cell. Biol. 1988 8:3129, Smith et al. Proc. Natl. Acad. Sci.USA 1985 82:8404, Miyajima et al. Gene 1987 58:273, and Martin et al.DNA 1988 7:99. Numerous baculoviral strains and variants andcorresponding permissive insect host cells from hosts are described inLuckow et al. Bio/Technology 1988 6:47-55, Miller et al. GENETICENGINEERING, Setlow, J. K. et al. eds., Vol. 8, Plenum Publishing, pp.1986 277-279, and Maeda et al. Nature 1985 315:592-594.

Mammalian expression can be accomplished as described in Dijkema et al.EMBO J. 1985 4:761, Gorman et al. Proc. Natl. Acad. Sci. USA 198279:6777, Boshart et al. Cell 1985 41:521, and U.S. Pat. No. 4,399,216.Other features of mammalian expression can be facilitated as describedin Ham et al. Meth. Enz. 1979 58:44, Barnes et al. Anal. Biochem. 1980102:255, U.S. Pat. Nos. 4,767,704, 4,657,866, 4,927,762, 4,560,655 andReissued U.S. Pat. No. RE 30,985, and in International Publication Nos.WO 90/103430, WO 87/00195.

The production of recombinant adenoviral vectors are described in U.S.Pat. No. 6,485,958.

Botulinum toxin type A can be obtained by establishing and growingcultures of Clostridium botulinum in a fermenter and then harvesting andpurifying the fermented mixture in accordance with known procedures.

Any of the above-described protein production methods can be used toprovide the biologic that would benefit from the present invention.

Pharmacology and Utility

The compounds of the invention are selective inhibitors of cysteineproteases such as cathepsin S, K, B, and/or F, and in particularcathepsin S, and accordingly are useful for treating diseases in whichcysteine protease activity contributes to the pathology and/orsymptomatology of the disease. For example, the compounds of theinvention are useful in treating autoimmune disorders, including, butnot limited to, juvenile onset diabetes, psoriasis, multiple sclerosis,pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupuserythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis,allergic disorders, including, but not limited to, asthma, allogeneicimmune responses, including, but not limited to, organ transplants ortissue grafts and endometriosis.

Cathepsin S is also implicated in disorders involving excessiveelastolysis, such as chronic obstructive pulmonary disease (e.g.,emphysema), bronchiolitis, excessive airway elastolysis in asthma andbronchitis, pneumonities and cardiovascular disease such as plaquerupture and atheroma. Cathepsin S is implicated in fibril formation and,therefore, inhibitors of cathepsins S are of use in treatment ofsystemic amyloidosis.

The cysteine protease inhibitory activities of the compounds of Formula(I) can be determined by methods known to those of ordinary skill in theart. Suitable in vitro assays for measuring protease activity and theinhibition thereof by test compounds are known. Typically, the assaymeasures protease-induced hydrolysis of a peptide-based substrate.Details of assays for measuring protease inhibitory activity are setforth in Biological Examples 1-5, infra.

Administration and Pharmaceutical Compositions

In general, compounds of Formula (I) will be administered intherapeutically effective amounts via any of the usual and acceptablemodes known in the art, either singly or in combination with one or moretherapeutic agents. A therapeutically effective amount may vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Forexample, therapeutically effective amounts of a compound of Formula (I)may range from about 10 micrograms per kilogram body weight (μg/kg) perday to about 100 milligram per kilogram body weight (mg/kg) per day,typically from about 100 μg/kg/day to about 10 mg/kg/day. Therefore, atherapeutically effective amount for an 80 kg human patient may rangefrom about 1 mg/day to about 8 g/day, typically from about 1 mg/day toabout 800 mg/day. In general, one of ordinary skill in the art, actingin reliance upon personal knowledge and the disclosure of thisApplication, will be able to ascertain a therapeutically effectiveamount of a compound of Formula (I) for treating a given disease.

The compounds of Formula (I) can be administered as pharmaceuticalcompositions by one of the following routes: oral, systemic (e.g.,transdermal, intranasal or by suppository) or parenteral (e.g.,intramuscular, intravenous or subcutaneous). Compositions can take theform of tablets, pills, capsules, semisolids, powders, sustained releaseformulations, solutions, suspensions, elixirs, aerosols, or any otherappropriate composition and are comprised of, in general, a compound ofFormula (I) in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the activeingredient. Such excipient may be any solid, liquid, semisolid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk, and the like. Liquid and semisolid excipientsmay be selected from water, ethanol, glycerol, propylene glycol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesameoil, and the like). Preferred liquid carriers, particularly forinjectable solutions, include water, saline, aqueous dextrose andglycols.

The amount of a compound of Formula (I) in the composition may varywidely depending upon the type of formulation, size of a unit dosage,kind of excipients and other factors known to those of skill in the artof pharmaceutical sciences. In general, a composition of a compound ofFormula (I) for treating a given disease will comprise from 0.01% w to90% w, preferably 5% w to 50% w, of active ingredient with the remainderbeing the excipient or excipients. Preferably the pharmaceuticalcomposition is administered in a single unit dosage form for continuoustreatment or in a single unit dosage form ad libitum when relief ofsymptoms is specifically required. Representative pharmaceuticalformulations containing a compound of Formula (I) are described below.

EXAMPLES

The present invention is further exemplified, but not limited by, thefollowing examples that illustrate the preparation of compounds ofFormula (I) (Examples) and intermediates (References) according to theinvention.

Reference A Synthesis of trifluoromethanesulfonic acid2,2,2-trifluoro-1-(4-fluorophenyl)ethyl ester

Step 1

To a stirred solution of 2,2,2,4′-tetrafluoroacetophenone (10 g, 52.1mmol) in methanol (50 mL) was added NaBH₄ (0.98 g, 26.5 mmol) at 0° C.After stirring at 25° C. for 2 h, the reaction mixture was quenched byadding 1N HCl (100 mL) and then extracted with ethyl ether. The etherextract was washed with brine, dried with MgSO₄, and concentrated togive 2,2,2-trifluoro-1-(4-fluorophenyl)ethanol (11.32 g) which was usedin next step without further purification.

Step 2

NaH (640 mg, 16 mmol, 60% in mineral oil) was washed twice with hexane(20 mL) and then suspended in dried diethyl ether (20 mL). A solution of2,2,2-trifluoro-1-(4-fluorophenyl)ethanol (1.94 g, 10 mmol) in diethylether (10 mL) was added at 0° C. After stirring for 2 h at roomtemperature, a solution of trifluoromethanesulfonyl chloride (1.68 g, 10mmol) in diethyl ether (10 mL) was added. After 2 h, the reactionmixture was quenched by adding a solution of NaHCO₃ and the product wasextracted with diethyl ether. The extracts were washed with brine anddried, and the solvent was removed to yield trifluoromethanesulfonicacid 2,2,2-trifluoro-1-(4-fluorophenyl)ethyl ester (3.3 g).

Reference B Synthesis of 2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethanol

To a −78° C. toluene (25 mL)/dichloromethane (25 mL) solution of2,2,2,4′-tetrafluoroacetophenone (2.5 g, 13.01 mmol) and 1M S-methyl CBSoxazaborolidine catalyst (1.3 mL, 1.3 mmol) was added freshly distilledcatecholborane (1.66 mL, 15.62 mmol). The reaction mixture wasmaintained at −78° C. for 16 h at which time 4N HCl (5 mL in dioxane)was added and the reaction mixture was allowed to warm to roomtemperature. The reaction mixture was diluted with ethyl acetate andwashed with a saturated brine solution. The organic layer was dried overmagnesium sulfate, filtered and concentrated to provide a solid. Thesolid was suspended in hexanes and filtered off. The hexanes filtratecontaining the desired product was concentrated and the residuesubjected to flash chromatography (10 hexanes:1 ethylacetate) to providethe title compound as colorless oil (2.2g, 87% yield). The ratio ofenantiomers was determined to be 95:5 by chiral HPLC (Chiralcel ODcolumn, 95 hexanes:5 isopropanol mobile phase. Ret. time major product6.757 min. Ret. time minor isomer 8.274 min.).

Reference D Synthesis of2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenypethylamino]-3-tritylsulfanylpropionicacid

To a slurry of S-trityl-L-cysteine (4.86 g, 13.37 mmol) indichloromethane (97 mL, 20 mL/g AA) at room temperature was addeddiisopropylethylamine (9.32 mL, 53.48 mmol) followed by a solution oftrifluoromethanesulfonic acid 2,2,2-trifluoro-1(RS)-phenylethyl ester(5.32 g, 16.04 mmol) (major enantiomer (S), 90 ee) in dichloromethane(15 mL) via syringe all at once. After 19 h, the reaction mixture wasconcentrated on the rotovap to give an oil. Diethyl ether was added andthe solution was washed with 1N HCl and brine. The organic layer wasdried over MgSO₄, filtered, and concentrated. Flash chromatography ofthe residue with 2 hexanes/1 ethyl acetate/0.25% acetic acid as theeluent provided2(R)-[2,2,2-trifluoro-1(RS)-(4-fluorophenyl)ethylamino]-3-tritylsulfanyl-propionicacid (6 g) (major diastereomer (R,S), 90 de) as an oil/foam.

Reference E Synthesis of2-(1-aminocyclopropyl)-N-cyclopropyl-2-hydroxyacetamide

Step 1

1-Aminocyclopropanecarbonitrile chlorohydrate (6.1 g, 51.4 mmol) wasrefluxed in 6N hydrochloric acid (500 mL) for 7 h and then concentratedto yield 1-aminocyclopropane-carboxylic acid chlorohydrate as anoff-white solid which was used in the next step without furtherpurification.

Step 2

A solution of 1-aminocyclopropanecarboxylic acid chlorohydrate (3.6 g,26.2 mmol) in MeOH (100 mL), containing potassium carbonate (4.0 g,28.94 mmol) was stirred at room temperature for 48 h. After filtration,MeOH was removed under reduced pressure to yield1-aminocyclopropanecarboxylic acid (2.64 g) which was used in the nextstep without further purification.

Step 3

1-Aminocyclopropanecarboxylic acid (2.64 g, 26.1 mmol) andtetramethylammonium hydroxide (2.38 g, 26.1 mmol) was added toacetonitrile (150 mL). The reaction mixture became homogeneous afterstirring at room temperature for about an hour. Boc₂O (8.54 g, 39.2mmol) was then added and stirring was continued for 2 days. On the3^(rd) day, another portion of Boc₂O (2.85 g, 13.1 mmol) was added andthe reaction mixture stirred an additional day. Acetonitrile was removedunder reduced pressure and the residue was partitioned between H₂O andEt₂O. The aqueous layer was washed with Et₂O and then acidified withsolid citric acid to pH ˜3. The aqueous solution was extracted withEtOAc. The combined EtOAc extracts were washed with brine, dried(Na₂SO₄), and the EtOAc was removed under reduced pressure to give1-tert-butoxycarbonylaminocyclopropanecarboxylic acid as a white solid(2.32 g) which was used in the next step without further purification.

Step 4

To a solution of 1-tert-butoxycarbonylaminocyclopropanecarboxylic acid(2.32 g, 11.5 mmol) in CH₂Cl₂ (25 mL) at 0° C. was addedN,O-dimethylhydroxylamine hydrochloride (1.24 g, 12.7 mmol),triethylamine (2.57 g, 3.54 mL, 25.4 mmol), and HATU (4.82 g, 12.7mmol). The reaction mixture was stirred at room temperature for 4 h. Thereaction mixture was concentrated under reduced pressure and thenpartitioned between Et₂O and water. The water layer was extracted withEt₂O. The combined organic layer was washed with brine, dried (Na₂SO₄),and concentrated under reduced pressure to yield[1-(methoxy-methyl-carbamoyl)-cyclopropyl]carbamic acid tert-butyl esterwhich was used in the next step without further purification.

Step 5

To a 0.05 M solution of[1-(methoxy-methyl-carbamoyl)cyclopropyl]carbamic acid tert-butyl esterin Et₂O (80 mL, 4.0 mmol) at room temperature was added dropwise lithiumaluminum hydride (1.0 M in Et₂O, 5 mL, 5.0 mmol). The reaction mixturewas stirred for another 20 min and then quenched with 6 mL of a solutionof KHSO₄ in water. The layers were separated and the aqueous layer wasextracted with Et₂O. The combined organic layers were washed with 1 NHCl, saturated NaHCO₃, and brine, dried (Na₂SO₄), and concentrated toyield (1-formylcyclopropyl)carbamic acid tert-butyl ester as a colorlessoil (393 mg) which was used immediately in the next step without furtherpurification.

Step 6

To a solution of (1-formylcyclopropyl)carbamic acid tert-butyl ester(393 mg, 2.12 mmol) in CH₂Cl₂ (4 mL) was added acetic acid (191 mg,0.182 mL, 3.18 mmol), and cyclopropyl isocyanide (142 mg, 2.12 mmol).The reaction mixture was stirred overnight at room temperature and thenconcentrated under reduced pressure to yield crude acetic acid(1-tert-butoxycarbonylaminocyclopropyl)cyclopropylcarbamoyl methyl esterwhich was used in the next step without further purification.

Step 7

To a solution of the acetic acid(1-tert-butoxycarbonylaminocyclopropyl)cyclopropylcarbamoyl methyl esterin MeOH (5 mL) was added 10% NaOH (1 mL). The reaction mixture wasstirred at room temperature for 2 h and then acidified with 2.5N HCl topH 7. The solution was extracted with EtOAc, washed with brine, dried(Na₂SO₄), and concentrated under reduced pressure to yield[1-(cyclopropylcarbamoylhydroxymethyl)cyclopropyl]-carbamic acidtert-butyl ester as a yellow oil which was used in the next step withoutfurther purification.

Step 8

A solution of [1-(cyclopropylcarbamoylhydroxymethyl)cyclopropyl]carbamicacid tert-butyl ester in CH₂Cl₂ (5 mL) and TFA (5 mL) was stirred atroom temperature for 2.5 h. The reaction mixture was concentrated andchased with toluene to yield2-(1-aminocyclopropyl)-N-cyclopropyl-2-hydroxyacetamide.

Proceeding as described in Steps 3-8 above but substituting1-aminocyclopropanecarboxylic acid with 1-aminocyclohexanecarboxylicacid provided 2-(1-aminocyclohexyl)-N-cyclopropyl-2-hydroxyacetamide.

Reference F Synthesis of3-amino-N-cyclopropyl-2-hydroxy-3-methylbutyramide

Step 1

To a solution of (2-hydroxy-1,1-dimethylethyl)-carbamic acid tert-butylester (284 mg, 1.5 mmol) in CH₂Cl₂ (5 mL) was added at 0° C. Dess-Martinperiodane (763 mg, 1.8 mmol). After 1.5 h, a solution of 0.26M Na₂S₂O₃in saturated NaHCO₃ (6 mL) was added and the resulting mixture wasstirred for 15 min. The layers were separated and the aqueous layer wasextracted with CH₂Cl₂. The combined organic layers were dried (Na₂SO₄)and concentrated to yield (1,1-dimethyl-2-oxo-ethyl)carbamic acidtert-butyl ester as a white solid which was used in the next stepwithout further purification.

Step 2

To a solution of (1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butylester in CH₂Cl₂ was added acetic acid (180 mg, 0.172 mL, 3.0 mmol) andcyclopropyl isocyanide (101 mg, 1.5 mmol). The reaction mixture wasstirred overnight at room temperature and then concentrated to yieldcrude acetic acid2-tert-butoxycarbonylamino-1-cyclopropylcarbamoyl-2-methylpropyl esterwhich was used in the next step without further purification.

Step 3

To a solution of acetic acid2-tert-butoxycarbonylamino-1-cyclopropylcarbamoyl-2-methylpropyl esterin MeOH (10 mL) was added 10% NaOH (1.5 mL). The reaction mixture wasstirred at room temperature for 3 h and then acidified with 1NHydrochloric acid to pH 7. The reaction mixture was extracted withEtOAc. The organic layer was dried (Na₂SO₄) concentrated to yield(2-cyclopropylcarbamoyl-2-hydroxy-1,1-dimethylethyl)-carbamic acidtert-butyl ester which was used in the next step without furtherpurification.

Step 4

A solution of(2-cyclopropylcarbamoyl-2-hydroxy-1,1-dimethylethyl)-carbamic acidtert-butyl ester in CH₂Cl₂ (10 mL) and TFA (5 mL) was stirred at roomtemperature for 4 h. The reaction mixture was then concentrated andchased with toluene to yield3-amino-N-cyclopropyl-2-hydroxy-3-methylbutyramide.

Reference G Synthesis of 3-amino-N-benzyl-2-hydroxy-3-methylbutyramide

3-Amino-N-benzyl-2-hydroxy-3-methylbutyramide was made by the proceduredescribed for 3-amino-N-cyclopropyl-2-hydroxy-3-methylbutyramide bysubstituting cyclopropyl isocyanide with benzyl isocyanide.

Example 1 Synthesis of2-oxo-3(S)-{3-(pyridin-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-propionylamino}hexanoicacid cyclopropylamide

Step 1

Catecholborane (19.4 mL, 182 mmol) in dichloromethane (15 mL) was addedto a dichloromethane solution of S-methyl CBS oxazaborolidine (13 mL, 13mmol) and 2,2,2,4′-tetrafluoroacetopheone (18.2 mL, 130.13 mmol)dropwise at −78° C. in 30 min. The reaction mixture was stirred at −78°C. overnight. The reaction mixture was quenched with 4N HCl (13 mL) indioxane at −78° C., warmed up to room temperature and the solvent wasremoved under reduced pressure. 10% NaHSO₃ solution (200 mL) was addedto concentrate and the aqueous layer was extracted by hexane. Theorganic layer was washed by water and dried with MgSO₄. Solvent wasremoved under the reduced pressure to give2,2,2-trifluoro-1(R)-(4-fluorophenyl)-ethanol (20 g) as colorless oil(90% e.e.).

Step 2

NaH (11.87 g, 296.7 mmol) was added to Et₂O (700 mL) at 0° C. under N₂followed by addition of an Et₂O solution of2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethanol (44.3g, 228.2 mmol). Thereaction mixture was stirred for 10 min at 0° C. then 1 h at roomtemperature. Trifluoromethanesulfonyl chloride (50 g, 296.7 mmol) inEt₂O was added at 0° C. under N₂ and the reaction mixture was stirred 10min at 0° C. then 3 h at room temperature. The solvent was removed underthe reduced pressure and H₂O (100 mL) was added slowly. The aqueouslayer was extracted by hexane and the combined organic layer was driedover MgSO₄. The solvent was removed under the reduced pressure to givetrifluoromethanesulfonic acid 2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethylester (70 g) as colorless oil.

Step 3

2(R)-Amino-3-tritylsulfanylpropionic acid (78 g, 214.6 mmol) wasdissolved in CH₂Cl₂ and DIPEA (112 mL, 643.8 mmol) was added and thereaction mixture was stirred for 10 min at room temperature.Trifluoromethanesulfonic acid 2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethylester (70 g, 214.6 mmol) in CH₂Cl₂ was added and the reaction mixturewas stirred overnight at room temperature. Solvent was removed under thereduced pressure and the residue was dissolved in Et₂O and washed with1N HCl, brine and dried over MgSO₄. Solvent was removed give2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenypethylamino]-3-tritylsulfanylpropionicacid (90 g as a yellow solid.

Step 4

2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenypethylamino]-3-tritylsulfanylpropionicacid (5.4 g, 10 mmol) was dissolved in CH₂Cl₂ and TFA (3.1 mL, 40 mmol)was added at 0° C. under N₂. Et₃SiH (3.2 mL, 20 mmol) was added at 0° C.under N₂ and the reaction mixture was warmed up to room temperature.After stirring for 2 h, the solvent was removed under the reducedpressure and the residue was dissolved in 1N NaOH (120 mL). The aqueouslayer was extracted with hexane. To the aqueous solution dioxane (120mL), 3-picolyl chloride hydrochloride (1.97 g, 12 mmol), andtris(2-carboxyethyl)phosphine hydrochloride (280 mg, 1 mmol) were added.The reaction mixture was stirred at room temperature overnight. Dioxanewas removed under the reduced pressure. The aqueous solution wasadjusted to pH 3 and was extracted with ethyl acetate. The combinedorganic extracts were dried over MgSO₄, filtered and concentrated underthe reduced pressure to give3-(pyridin-3-ylmethanesulfanyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)-ethylamino]propionicacid which was used in the next step without further purification.

Step 5

To a solution of3-(pyridin-3-ylmethanesulfanyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)-ethylamino]propionicacid in methanol (10 mL), an aqueous solution of OXONE® (4.68g, 15 mmolin 10 mL H₂O) was added. The reaction mixture was stirred at roomtemperature. After 2 h, solvent was removed under reduced pressure. Theaqueous layer was extracted with ethyl acetate and the combined organicextracts were was washed with brine and dried with MgSO₄ and filteredThe filtrate was concentrated under the reduced pressure to give3-(pyridin-3-ylmethanesulfonyl)-2-(R)[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionicacid which was used in the next step without further purification.

Step 6

A mixture of3-(pyridin-3-ylmethanesulfonyl)-2-(R)[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionicacid (420 mg, 1 mmol), 3(S)-amino-2-hydroxyhexanoic acidcyclopropylamide (186 mg, 1 mmol) prepared as described in PCTapplication publication No. WO-02/18369 as compound xiii, HBTU (455 mg,1.2 mmol), and NMM (0.44 mL, 4 mmol) in acetonitrile was stirred at roomtemperature overnight. Sat. NH₄Cl (10 mL) and ethyl acetate (10 mL) wereadded and after 20 min the aqueous layer was extracted with ethylacetate. The combined organic extracts were washed with brine and driedwith MgSO₄, filtered and the filtrated was concentrated under thereduced pressure to give2-hydroxy-3(S)-{3-(pyridin-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)-ethylamino]propionylamino}-hexanoicacid cyclopropylamide which was used in the next step without furtherpurification.

Step 7

To a solution of2-hydroxy-3(S)-{3-(pyridin-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionylamino}hexanoicacid cyclopropylamide (590 mg, 1 mmol) in methylene chloride, DMP wasadded slowly. The reaction mixture was stirred at room temperature for30 min and then a 0.26 M Na₂S₂O₃ in sat. NaHCO₃ was added. The reactionmixture was stirred for 20 min. The aqueous layer was extracted withmethylene chloride and the combined organic extracts were dried overMgSO₄, filtered and concentrated to give2-oxo-3(S)-{3-(pyridin-3-ylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-propionylamino}hexanoicacid cyclopropylamide which was purified by flash column (2%MeOH—CH₂Cl₂) to give pure product as a yellow solid.

¹H-NMR(DMSO-d₆): δ 0.80(m, 12H), 2.02(m, 1H), 3.3-3.7(b, 3H), 4.00(m,1H), 4.46(m, 1H), 4.79(m, 2H), 7.25(m, 2H), 7.50(m, 2H), 7.65(b, 1H),7.72(d, 1H), 8.01(d, 1H), 8.71(m, 3H). LC-MS: 587(M+1), 585, (M−1),609(M+23).

Proceeding as described above but substituting 3-picolyl chloride withcyclopropylmethyl bromide provided2-oxo-3(S)-{3-(cyclopropylmethanesulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-propionylamino}hexanoicacid cyclopropylamide (compound 1). ¹H-NMR(DMSO-d₆): δ 0.32-0.41 (m,2H), 0.53-0.67 (m, 6H), 0.81(t, J=7.2 Hz, 3H), 1.06-1.38 (m, 4H),1.52-1.61 (m, 1H), 2.69-2.76 (m, 1H), 2.98 (dd, J=2.8 Hz, J=14.8 Hz,1H), 3.19 (dd, J=8 Hz, J=14 Hz, 1H), 3.28-3.50 (m, 3H), 3.82-3.88 (m,1H), 4.37 (quint, J=7.6 Hz, 1H), 4.70-4.76 (m, 1H), 7.22 (t, J=8.4 Hz,2H), 7.43 (dd, J=5.6 Hz, J=8.4 Hz, 2H), 8.51 (d, J=7.2 Hz, 1H), 8.73 (d,J=5.2 Hz, 1H). LC-MS: 550(M+1), 548, (M−1).

Example 2 Synthesis of2-oxo-3(S)-3-[2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridyl-3-ylmethanesulfonyl)propionylamino]pentanoicacid cyclopropylamide

Step 1

To a −78° C. methylene chloride solution (75 mL) of2,2,3,3,3-pentafluoropropan-1-ol (1.5 g, 10.0 mmol) and DIPEA (6.1 mL,35.0 mmol) was added triflic anhydride (1.78 mL, 10.5 mmol). After 2.5h, S-tritylcysteine was added all at once and the reaction mixture wasstirred at 0° C. for 80 min. The reaction mixture was stirred at RT for18 h and then concentrated on the rotovap. Ethyl acetate was added andthe reaction mixture was washed with 1N HCl. The organic layer was driedover magnesium sulfate, filtered and concentrated. The crude product waspurified by flash chromatography (3 hexanes/1 ethyl acetate+1% aceticacid) to provide2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-tritylsulfanylpropionic acid(3.29 g).

Step 2

To a methylene chloride solution (15 mL) of2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-tritylsulfanylpropionic acid(1.05 g, 2.12 mmol) was added TFA (0.653 mL, 8.48 mmol) followed bytriethylsilane (0.677 mL, 4.24 mmol). The reaction mixture was stirredfor 1.5 h at room temperature and then concentrated on the rotovap. Tothe residue was added 2N NaOH solution (20 mL) and the reaction mixturewas extracted with hexanes. To the NaOH layer was addedtris(2-carboxytriethyl)phosphine hydrochloride (60 mg) followed by3-picolylchloride hydrochloride (348 mg, 2.12 mmol). After 1.5 h, thereaction mixture was acidified with conc. HCl to ˜pH=4 and extractedwith ethyl acetate. The organic layer was dried and concentrated to give2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridin-3-ylmethanesufanyl)propionicacid (530 mg).

Step 3

To a methylene chloride solution of2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridin-3-ylmethanesufanyl)propionicacid (151 mg, 0.44 mmol), 3(S)-amino-2-hydroxypentanoic acidcyclopropylamide hydrochloride (92 mg, 0.44 mmol), EDC (102 mg, 0.66mmol), and HOBt hydrate (71 mg, 0.53 mmol) was added N-methylmorpholine(0.194 mL, 1.76 mmol). The reaction mixture was stirred for 2 h and thendiluted with ethyl acetate and washed with sodium bicarbonate solution.Concentration of the organic layer gave2-hydroxy-3(S)-[2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridin-3-ylmethanesulfanyl)propionylamino]hentanoicacid cyclopropylamide (170 mg).

Step 4

To an NMP solution of2-hydroxy-3(S)-[2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridin-3-ylmethanesulfanyl)propionylamino]pentanoicacid cyclopropylamide (170 mg, 0.34 mmol) was added an aqueous solutionof OXONE® (209 mg, 0.34 mmol). After 2 h, more OXONE® (105 mg, 0.17mmol) was added with additional water plus some methanol. After anadditional 1 h 40 min, the reaction mixture was diluted with ethylacetate and washed with water. Concentration of the organic layerprovided2-hydroxy-3(S)-[2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridin-3-ylmethylsulfonyl)propionylamino]pentanoicacid cyclopropylamide (176 mg).

Step 5

To a heterogeneous mixture of2-hydroxy-3(S)-[2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridin-3-ylmethanesulfonyl)propionylamino]pentanoicacid cyclopropylamide (176 mg, 0.33 mmol) in methylene chloride wasadded Dess-Martin periodinane (183 mg, 0.43 mmol). The reaction mixturebecame more heterogeneous after a couple of minutes. After 3 h,acetonitrile (3 mL) was added followed by NMP (6 mL) to give ahomogeneous reaction. Additional Dess-Martin periodinane was added atthis time (100 mg). After an additional 70 min of stirring, the reactionmixture was diluted with ethyl acetate and washed with sodiumbicarbonate solution. The organic layer was separated and concentrated.Flash chromatography (95% methylene chloride/5% methanol) of the residueprovided a solid which was suspended in a 1:1 IPA/ethanol mixture andallowed to evaporate to dyness to provide2-oxo-3(5)-3-[2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridyl-3-ylmethanesulfonyl)propionylamino]pentanoicacid cyclopropylamide (87 mg).

Example 3 Synthesis ofN-(1-cyclopropylaminooxalylcyclopropyl)-3-cyclopropylmethanesulfonyl-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionamide

Step 1

To a solution of3-cyclopropylmethanesulfanyl-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-propionicacid (148 mg, 0.42 mmol), prepared as described in example 1 above, bysubstituting picolyl chloride with cyclopropylmethyl bromide, and2-(1-aminocyclopropyl)-N-cyclopropyl-2-hydroxyacetamide (108 mg, 0.63mmol) in N-methylpyrrolidine (6 mL) at 0° C. was addedN,N-diethylpropylamine (272 mg, 0.37 mL, 2.11 mmol), and HATU. Thereaction mixture was stirred 4 hours at room temperature. The reactionmixture was diluted with EtOAc and washed with H₂O. The organic layerwas dried (Na₂SO₄) and concentrated to yieldN-[1-(cyclopropylcarbamoyl-hydroxy-methypcyclopropyl]-3-cyclopropylmethylsulfanyl-2-[2,2,2-trifluoro-1-(4-fluorophenyl)-ethylamino]propionamidewhich was converted to the title compound as described in Example 2,steps 4 and 5 above. MS (534.2 M+1, 532.1 M−1).

Follwing the procedure described in Example 3 above but substituting2-(1-aminocyclopropyl)-N-cyclopropyl-2-hydroxyacetamide with3-amino-N-benzyl-2-hydroxy-3-methylbutyramide providedN-benzyl-3-{3-cyclopropylmethanesulfonyl-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionylamino}-3-methyl-2-oxo-butyramide.MS (586.3 M+1, 584.3 M−1).

Follwing the procedure described in Example 3 above but substituting2-(1-aminocyclopropyl)-N-cyclopropyl-2-hydroxyacetamide with3-amino-N-benzyl-2-hydroxy-3-methylbutyramide and2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionicacid with2(R)-[2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionicacid providedN-benzyl-3-{3-cyclopropylmethanesulfonyl-2(R)-[2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethylamino]propionylamino}-3-methyl-2-oxo-butyramide.N-Benzyl-3-{3-cyclopropylmethanesulfonyl-2-[2,2,2-tiifluoro-1-(4-fluoro-phenyl)-ethylamino]-propionylamino}-3-methyl-2-oxo-butyramideMS (586.1 M+1, 584.1 M−1).

Follwing the procedure described in Example 3 above but substituting2-(1-amino-cyclopropyl)-N-cyclopropyl-2-hydroxyacetamide with3-amino-N-cyclopropyl-2-hydroxy-3-methylbutyramide providedN-cyclopropyl-3-{3-cyclopropylmethanesulfonyl-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionylamino}-3-methyl-2-oxo-butyramide.MS (536.0 M+1, 534.2 M−1).

Example 4 Synthesis of3(S)-[3-cyclopropylmethanesulfonyl-2(R)-(2,2,3,3,3-pentafluoropropylamino)-propionylamino]-2-oxo-pentanoicacid cyclopropylamide

Step 1

To a −78° C. dichloromethane solution (75 mL) of2,2,3,3,3-pentafluoropentan-1-ol (1.5 g, .10.0 mmol) and DIPEA (6.1mL,35.0 mmol) was added triflic anhydride (1.78 mL, 10.5 mmol) dropwise.After 2 h and 20 min, S-trityl cysteine was added to the reaction andstirring continued for 1 h and 15 min at ° C. and then 19 h at roomtemperature. The reaction mixture was concentrated on the rotovap andthe residue was subjected to flash chromatography (3:1, hexanes/ethylacetate with 1% acetic acid) to provide2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-tritylsulfanylpropionic acid(3.29g).

Step 2

To a dichloromethane solution of2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-tritylsulfanylpropionic acid(1.05 g, 2.12 mmol) was added TFA (0.653 mL, 8.48 mmol) followed bytriethylsilane (0.677 mL, 4.24 mmol). The reaction mixture was stirredfor 1 h and 20 min at room temperature and then concentrated on therotovap. To the residue was added 2N NaOH and hexanes. The mixture wasshaken and the NaOH layer separated. To the NaOH layer was addedcyclopropylmethyl bromide (0.206 mL, 2.12 mmol). The reaction mixturewas stirred for 17 h at room temperature and then acidified with 1N HCland the product extracted into ethylacetate. The ethyl acetate layer waswashed with brine, dried over magnesium sulfate, filtered andconcentrated to provide2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(cyclopropylmethanesulfanyl)propionicacid (428 mg).

Step 3

To a mixture of2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(cyclopropylmethanesulfanyl)propionicacid (150 mg, 0.49 mmol), 3(S)-amino-2-hydroxy-pentanoic acidcyclopropylamide hydrochloride (102 mg, 0.49 mmol), EDC (114 mg, 0.74mmol)and HOBt (79 mg, 0.59 mmol) in dichlormethane was addedN-methylmorpholine (0.215 mL, 1.96 mmol). The reaction mixture wasstirred for 2 h at room temperature and then diluted with ethylacetateand washed with sodium bicarbonate solution. The organic layer was driedand concentrated to provide2-hydroxy-3(S)-[2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(cyclopropylmethanesulfanyl)propionylamino]pentanoicacid cyclopropylamide (169 mg).

Step 4

To an NMP solution (5 mL) of2-hydroxy-3(S)-[2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(cyclopropylmethanesulfanyl)propionylamino]pentanoicacid cyclopropylamide (169 mg, 0.37 mmol) was added an aqueous solution(5 mL) of OXONE (342 mg, 0.56 mmol). After stirring for 2 h at roomtemperature more aqueous OXONE (228 mg) was added along with methanol (5mL). After stirring for additional 2 h the reaction was diluted withethylacetate and washed with a sat'd brine solution. The organic layerwas separated, dried and concentrated to provide a white solid to whichwas added dichloromethane (10 mL) and Dess-Martin periodane. To thisheterogeneous mixture was added acetonitrile (3 mL) followed by NMP (6mL) which provided a homogeneous reaction. After 5 h, the reaction wasdiluted with ethylacetate and washed with sodium bicarbonate solution.The organic layer was dried and concentrated to provide the crudeproduct as a white solid. To this white solid was added ethanol and themixture was heated to reflux. The still heterogeneous mixture wasallowed to cool to room temperature and was filtered to provide thetitle compound as a white solid (115 mg). M. pt 196.1-196.7° C.

Proceeding as above the following compounds were prepared:

N-cyclopropyl-3S-{3-benzenesulfonyl-2R-[2,2,2-trifluoro-1S-(4-fluoro-phenyl)-ethylamino]-propionylamino}-2-oxo-pentanamide,LC-MS 558(M+H); and

N-cyclopropyl-3S-[3-cyclopropylmethanesulfonyl-2R-(2,2,3,3,4,4,4-heptafluorobutylamino)-propionylamino]-2-oxo-pentanamide,LC-MS 542(M+H).

Example 5 Syntheis ofN-cyclopropyl-3S-{4-methanesulfonyl-2S-[2,2,2-trifluoro-1S-(4-fluorophenyl)-ethylamino]-butyrylamino}-2-oxo-pentanamide

(S) Methyl 2-amino-4-methylsulfanylbutyrate hydrochloride (750 mg, 3.76mmol) and 2,2,2-trifluoro-1-(4-fluoro-phenyl)-ethanone (721 mg, 3.76mmol) was dissolved in methanol (15 mL) and then potassium carbonate(1.04 g, 7.52 mmol) was added to the solution. The mixture was stirredat 55° C. for 23 hours and then concentrated to dryness on a rotovap.The residue was combined with toluene (20 mL) and the mixture wasconcentrated to dryness on a rotovap. The residue was combined withacetonitrile (10 mL) and the mixture was stirred at approximately −30°C. Zinc borohydride, prepared by adding a 1M zinc chloride solution inether (5.64 mL) to a mixture of sodium borohydride (427 mg, 11.28 mmol)stirring in ether (10 mL) and then stirring this mixture 19 hours, wasadded and the reaction stirred for approximately 7 hours at reducedtemperature and then an additional 16 hours at room temperature. Thereaction mixture was quenched with 1N HCl, diluted with ethyl acetate,and washed with brine (2×50 mL). The organic layer was dried andconcentrated to provide2S-[2,2,2-trifluoro-1S-(4-fluorophenyl)ethylamino]-4-methylsulfanylbutyricacid (1.15 g) as solid.

2S-[2,2,2-Trifluoro-1S-(4-fluorophenyl)ethylamino]-4-methylsulfanylbutyricacid (150 mg, 0.46 mmol), cyclopropyl 3S-amino-2-hydroxypentanamidehydrochloride (106 mg, 0.51 mmol), EDC (132 mg, 0.69 mmol) and HOBt (75mg, 0.55 mmol) were combined in DCM (10 mL) and the mixture was stirredat room temperature while N-methylmorpholine (0.253 mL, 2.3 mmol) wasadded. The mixture was stirred for 2 hours and 15 minutes and thendiluted with ethyl acetate. The mixture was washed with sodiumbicarbonate solution (2×35 mL) and the organic layer was dried andconcentrated to provide N-cyclopropyl-2-hydroxy-3S-{4-methylsulfanyl2S[2,2,2-trifluoro-1S-(4-fluoro-phenyl)-ethylamino]-butyrylamino}-pentanamide(188 mg) as a white solid.

N-Cyclopropyl-2-hydroxy-3S-{4-methylsulfanyl 2S-[2,2,2-trifluoro-1S-(4-fluoro-phenyl)-ethylamino]-butyrylamino}-pentanamide (188 mg, 0.39mmol) was dissolved in 1-methyl-2-pyrrolidinone (5 mL) and the solutionwas stirred at room temperature while an aqueous solution of oxone (5mL, 434 mg, 0.71 mmol) was added. The mixture was stirred for 1 hour and45 minutes and then diluted with ethyl acetate. The mixture was washedwith brine (3×25 mL) and the organic layer was dried and concentrated.The residue was dissolved in 1-methyl-2-pyrrolidinone (5 mL) and thenDess-Martin (232 mg, 0.55 mmol) was added to the solution. The reactionwas allowed to proceed for 1 hour and then the solution was diluted withethyl acetate. The mixture was washed with sodium bicarbonate solution(3×30 mL) and the organic layer was dried and concentrated. The residuewas combined with ether. The mixture was scraped and filtered to provideN-cyclopropyl-3S-{4-methanesulfonyl-2S[2,2,2-trifluoro-1S-(4-fluoro-phenyl)-ethylamino]-butyrylamino}-2-oxo-pentanamide(114 mg) as a white solid (mp 152.5-153.5 ° C.). LC-MS 510(M+H).

Biological Examples Example 1 Cathepsin B Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid(BES), 50 mM (pH 6); polyoxyethylenesorbitan monolaurate, 0.05%; anddithiothreitol (DTT), 2.5 mM). Human cathepsin B (0.025 pMoles in 25 μLof assay buffer) was added to the dilutions. The assay solutions weremixed for 5-10 seconds on a shaker plate, covered and incubated for 30min at room temperature. Z-FR-AMC (20 nMoles in 25 μL of assay buffer)was added to the assay solutions and hydrolysis was followedspectrophotometrically at (λ 460 nm) for 5 min. Apparent inhibitionconstants (K_(i)) were calculated from the enzyme progress curves usingstandard mathematical models.

Compounds of the invention were tested by the above-described assay andobserved to exhibit cathepsin B inhibitory activity.

Example 2 Cathepsin K Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).Human cathepsin K (0.0906 pMoles in 25 μL of assay buffer) was added tothe dilutions. The assay solutions were mixed for 5-10 seconds on ashaker plate, covered and incubated for 30 min at room temperature.Z-Phe-Arg-AMC (4 nMoles in 25 μL of assay buffer) was added to the assaysolutions and hydrolysis was followed spectrophotometrically at (λ 460nm) for 5 min. Apparent inhibition constants (K_(i)) were calculatedfrom the enzyme progress curves using standard mathematical models.

Compounds of the invention were tested by the above-described assay andobserved to exhibit cathepsin K inhibitory activity.

Example 3 Cathepsin L Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: MES, 50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM).Human cathepsin L (0.05 pMoles in 25 μL of assay buffer) was added tothe dilutions. The assay solutions were mixed for 5-10 seconds on ashaker plate, covered and incubated for 30 min at room temperature.Z-Phe-Arg-AMC (1 nMoles in 25 μL of assay buffer) was added to the assaysolutions and hydrolysis was followed spectrophotometrically at (λ 460nm) for 5 min. Apparent inhibition constants (K_(i)) were calculatedfrom the enzyme progress curves using standard mathematical models.

Compounds of the invention were tested by the above-described assay andobserved to exhibit cathepsin L inhibitory activity.

Example 4 Cathepsin S Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100mM); β-mercaptoethanol, 2.5 mM; and BSA, 0.00%. Human cathepsin S (0.05pMoles in 25 μL of assay buffer) was added to the dilutions. The assaysolutions were mixed for 5-10 seconds on a shaker plate, covered andincubated for 30 min at room temperature. Z-Val-Val-Arg-AMC (4 nMoles in25 μL of assay buffer containing 10% DMSO) was added to the assaysolutions and hydrolysis was followed spectrophotometrically (at λ 460nm) for 5 min. Apparent inhibition constants (K_(i)) were calculatedfrom the enzyme progress curves using standard mathematical models.

Compounds of the invention were tested by the above-described assay andobserved to exhibit cathepsin S inhibitory activity of < or =100 nm.

Example 5 Cathepsin F Assay

Solutions of test compounds in varying concentrations were prepared in10 μL of dimethyl sulfoxide (DMSO) and then diluted into assay buffer(40 μL, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100mM); DTT, 2.5 mM; and BSA, 0.01%. Human cathepsin F (0.1 pMoles in 25 μLof assay buffer) was added to the dilutions. The assay solutions weremixed for 5-10 seconds on a shaker plate, covered and incubated for 30min at room temperature. Z-Phe-Arg-AMC (2 nMoles in 25 μL of assaybuffer containing 10% DMSO) was added to the assay solutions andhydrolysis was followed spectrophotometrically (at λ 460 nm) for 5 min.Apparent inhibition constants (K_(i)) were calculated from the enzymeprogress curves using standard mathematical models.

Compounds of the invention were tested by the above-described assay andobserved to exhibit cathepsin F inhibitory activity.

Example 1 Representative Pharmaceutical Formulations Containing aCompound of Formula (I)

ORAL FORMULATION Compound of Formula (I) 10-100 mg Citric AcidMonohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL

INTRAVENOUS FORMULATION Compound of Formula (I) 0.1-10 mg DextroseMonohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05 mg SodiumHydroxide 0.18 mg Water for Injection q.s. to 1.0 mL

TABLET FORMULATION Compound of Formula (I) 1% Microcrystalline Cellulose73% Stearic Acid 25% Colloidal Silica 1%

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

1. A compound of Formula (II):

wherein: R⁵ is alkyl, cycloalkylalkyl, aralkyl, heteroaralkyl,heterocycloalkylalkyl, -(alkylene)-X—R⁹ (where X is —S— or —SO₂— and R⁹is alkyl, cycloalkylalkyl, aryl, aralkyl or heteroaralkyl) or haloalkyloptionally substituted with cycloalkyl, wherein the aromatic oralicyclic ring in R⁵ is optionally substituted with one, two, or threeR^(a) independently selected from alkyl, haloalkyl, alkoxy, hydroxy,haloalkoxy, cyano, halo or —SO₂R¹¹ (where R¹¹ is alkyl, cycloalkyl,aryl, heteroaryl, or heterocycloalkyl); R⁶ is haloalkyl; and R⁸ ishydrogen or aryl, wherein the aromatic ring in R⁸ is optionallysubstituted with one, two, or three R^(e) independently selected fromalkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy, alkylcarbonyl,alkoxycarbonyl, carboxy, cyano, alkylsulfonyl, alkylsulfonylamino,aminocarbonyl, or aminosulfonyl; or a pharmaceutically acceptable saltsthereof.
 2. The compound of claim 1, wherein R⁵ is -(alkylene)-S—R⁹. 3.The compound of claim 1, wherein R⁵ is -(alkylene)-SO₂—R⁹.
 4. Thecompound of claim 1, wherein the compound is selected from:


5. The compound of claim 1, wherein the compound is selected from:


6. A compound of Formula (III):

wherein: R¹ is hydrogen; R² is cycloalkyl or aralkyl; R³ is hydrogen oralkyl; R⁴ is alkyl; or R³ and R⁴ together with the carbon atom to whichthey are attached form cycloalkylene; R⁵ is alkyl, cycloalkylalkyl,aralkyl, heteroaralkyl, heterocycloalkylalkyl, -(alkylene)-X—R⁹ (where Xis —S— or —SO₂— and R⁹ is alkyl, cycloalkylalkyl, aryl, aralkyl orheteroaralkyl) or haloalkyl optionally substituted with cycloalkylwherein the aromatic or alicyclic ring in R⁵ is optionally substitutedwith one, two, or three R^(a) independently selected from alkyl,haloalkyl, alkoxy, hydroxy, haloalkoxy, cyano, halo or —SO₂R¹¹ (whereR¹¹ is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl); R⁶ ishaloalkyl; and R⁸ is hydrogen or aryl, wherein the aromatic ring in R⁸is optionally substituted with one, two, or three R^(e) independentlyselected from alkyl, halo, haloalkyl, hydroxy, alkoxy, haloalkoxy,alkylcarbonyl, alkoxycarbonyl, carboxy, cyano, alkylsulfonyl,alkylsulfonylamino, aminocarbonyl, or aminosulfonyl; or apharmaceutically acceptable salts thereof.
 7. The compound of claim 6,wherein R⁵ is -(alkylene)-S—R⁹.
 8. The compound of claim 6, wherein R⁵is -(alkylene)-SO₂—R⁹.
 9. The compound of claim 6, wherein the compoundis selected from:


10. The compound of claim 6, wherein the compound is selected from: